1yu92
`NO.’LO
`VeRO
`0,0 becccctc SkhO? P3962000U0
`TI. PROCEEDINGS OF THE
`NATIONAL ACADEMY OF
`
`MAY15, 1992
`VOLUME89
`NUMBER10
`
`
`
`Proceedings
`OF THENational Academy
`of Sciences
`
`OF THE UNITED STATES OF AMERICA
`
`Pfizer Ex. 1008
`Page 1 of 14
`
`Pfizer Ex. 1008
`Page 1 of 14
`
`

`

`Proceedings
`OF THE
`National Academy
`of Sciences
`
`OF THE UNITED STATES OF AMERICA
`
`Officers
`of the
`Academy
`
`Editorial Board
`of the
`Proceedings
`
`FRANK Press, President
`James D. Epert, Vice President
`PETER H. RAVEN, Home Secretary
`JAMES B. WYNGAARDEN, Foreign Secretary
`ELKAN R, BLOUT, Treasurer
`
`RopertT H. ABELES
`MICHAEL J. CHAMBERLIN
`Icor B. DAwID
`RONALD L. GRAHAM
`
`LAWRENCE BocoraD, Chairman
`Gorbon G. HAMMES
`Eric R. KANDEL
`Puitie W. MAJERUS
`HERBERT A. SIMON
`
`MAXINE F, SINGER
`HAROLD VARMUS
`SHERMAN M. WEISSMAN
`
`Senior Contributing
`Editors:
`
`MICHAEL T. CLEGG, Eric R. KANDEL, ARNO G. MOTULSKY, PAUL R. SCHIMMEL,
`CHARLES F. STEVENS, IRVING L. WEISSMAN
`
`Contributing Editors:
`
`Max Cooper, HERMAN N., E1isen, LEroy Hoop, WILLIAM E. PAUL
`
`Consulting Editors:
`
`RAYMOND L. ERIKSON, JOSEPH L. GOLDSTEIN, Davip J. L. Luck, PHiLip W, MAJERUS,
`Davip D. SABATINI, ALLAN C, SPRADLING, SHERMAN I, WEISSMAN
`
`Managing Editor:
`Senior Associate Editor:
`Associate Editors:
`
`FRANCES R,. ZWANZIG
`Gary T. Cocks
`Cay Buter, JoHN M. MALLoY, MARILYN J. MASON, JANET L. MORGAN, T. PEARSON,
`Dorortuy P. SmitH, COLENE RUCH WALDEN
`Assistant Managing Editor: JOANNE D’ AMICO
`Senior Production Editor:
`BARBARA A. BACON
`Production Editors:
`JAMIE M. Fear, BILL FoGLe, Scott C. HERMAN, AtrJA OZOLINS, KATHLEEN Ruby,
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`
`Editorial Correspondence: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, 2101 Constitution Avenue, Wash-
`ington, DC 20418.
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`Information for Contributors: See p. i (of this issue) and pp. i~viii of Issue Number 1, January 1, 1992.
`Copyright: The National Academyof Sciences has copyrighted this journal as a collective work and does not own copyrights
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`should be addressed to the authors. Microforms of complete volumesare available to regular subscribers only and may be
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`This material was copied
`
`Pfizer Ex. 1008
`Page 2 of 14
`
`Pfizer Ex. 1008
`Page 2 of 14
`
`

`

`OF 7;
`o
`CEDOFTae
`ot
`
`La,
`
`Proceedings
`
`OF THE
`
`National Academy
`of Sciences
`OF THE UNITED STATES OF AMERICA
`
`
`pp. 4221-4780
`Volume 89, Number 10
`
`May 15, 1992
`
`Table of Contents
`
`CONDENSED INFORMATION FOR CONTRIBUTORS
`
`AUTHOR INDEX
`
`Physical Sciences
`
`CHEMISTRY
`
`On the structure of the nickel/iron/sulfur center of the carbon monoxide
`dehydrogenase from Rhodospirillum rubrum: An x-ray absorption
`spectroscopy study
`
`Semisynthetic combinatorial antibody libraries: A chemical solution to the
`diversity problem
`
`Identification of highest-affinity ligands by affinity selection from equimolar
`peptide mixtures generated by robotic synthesis
`
`Grace QO. Tan, Scott A. Ensign, Stefano
`Ciurli, Michael J. Scott, Britt Hedman,
`Richard H. Holm, Paul W. Ludden, Z.
`Richard Korszun, Philip J. Stephens,
`and Keith O. Hodgson
`Carlos F, Barbas HI, J. D. Bain,
`Denis M. Hoekstra,
`and Richard A. Lerner
`Ronald N. Zuckermann, Janice M. Kerr,
`Michael A. Siani, Steven C. Banville,
`and Daniel V. Santi
`
`xiFXiil
`
`4427-4431
`
`4457-4461
`
`4505-4509
`
`MATHEMATICS
`
`Approximating Markov chains
`
`Steven M. Pincus
`
`4432-4436
`
`iii
`
`Pfizer Ex. 1008
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`

`

`Contents
`
`Biological Sciences
`
`BIOCHEMISTRY
`
`MELASmutation in mtDNA binding site for transcription termination
`factor causes defects in protein synthesis and in respiration but no
`changein levels of upstream and downstream mature transcripts
`
`Alternative usageofinitiation codons in mRNA encoding the
`cAMP-responsive-element modulator generates regulators with
`Opposite functions
`
`Phosphorylationsites in the amino-terminal region of mouse p53
`Transformation and transactivation suppressoractivity of the c-Jun leucine
`zipper fused to a bacterial repressor
`
`Functional domains in Fok I restriction endonuclease
`
`The FixL protein of Rhizobium meliloti can be separated into a
`heme-binding oxygen-sensing domain and a functional C-terminal
`kinase domain
`
`Cloning of the low-affinity murine granulocyte~macrophage
`colony-stimulating factor receptor and reconstitution of a high-affinity
`receptor complex
`
`Direct association of pp40/I«BB with rel/NF-«B transcription factors: Role
`of ankyrin repeats in the inhibition of DNA binding activity
`
`A 33-kDa polypeptide with homology to the laminin receptor: Component
`of translation machinery
`Crystal structure of an engineered subtilisin inhibitor complexed with
`bovine trypsin
`
`A gene homologous to chloroplast carbonic anhydrase (icfA) is essential to
`photosynthetic carbon dioxide fixation by Synechococcus PCC7942
`Efficiency of binding the retinoblastoma protein correlates with the
`transforming capacity of the E7 oncoproteins of the
`humanpapillomaviruses
`Long-term agonist exposure induces upregulation of B3-adrenergic receptor
`expression via multiple CAMP response elements
`
`induction of apoptosis by wild-type p53 in a human colon tumor-derived
`cell
`line
`Peptidyl-prolyl cis-trans isomerase improves the efficiency of protein
`disulfide isomerase as a catalyst of protein folding
`Methods for the large-scale synthesis of psoralen furan-side monoadducts
`and diadducts
`Excretion of putrescine by the putrescine—ornithine antiporter encoded by
`the potE gene of Escherichia coli
`
`Cloning of the yeast FAS3 pene and primarystructure of yeast
`acetyl-CoA carboxylase
`
`The Escherichia coli chromosomecontains specific, unmethylated dam and
`demsites
`
`Modification of histidine residues in proteins by reaction
`with 4-hydroxynonenal
`Adenovirus ELA, simian virus 40 tumor antigen, and human papillomavirus
`E7 protein share the capacity to disrupt the interaction between
`transcription factor E2F and the retinoblastoma gene product
`
`A. Chomyn, A. Martinuzzi, M. Yoneda,
`A. Daga, O. Hurko, D. Johns, S. T.
`Lai, 1. Nonaka, C. Angelini,
`and G. Attardi
`
`Véronique Delmas, Brid M. Laoide,
`Denis Masquilier, Rolf P. de Groot,
`Nicholas S. Foulkes, and Paolo
`Sassone-Corsi
`
`Yeong Wang and Walter Eckhart
`Michéle Granger-Schnarr, Enrico
`Benusiglio, Manfred Schnarr,
`and Paolo Sassone-Corsi
`
`Lin Li, Louisa P. Wu, and Srinivasan
`Chandrasegran
`Ellen K. Monson, Michael Weinstein,
`Gary S. Ditta, and Donald R. Helinski
`
`Linda S. Park, Unja Martin,
`Rick Sorensen, Sean Luhr,
`Philip J. Morrissey, David Cosman,
`and Alf Larsen
`
`Jun-ichiro Inoue, Lawrence D. Kerr,
`Dana Rashid, Nathan Davis,
`HenryR. Bose, Jr.,
`and Inder M. Verma
`
`Dorothy Auth and George Brawerman
`
`Yasuo Takeuchi, Takamasa Nonaka,
`Kazuo T. Nakamura, Shuichi Kojima,
`Kin-ichiro Miura, and Yukio Mitsui
`
`Hideya Fukuzawa, Eyi Suzuki, Yutaka
`Komukai, and Shigetoh Miyachi
`Donald V. Heck, Carole L. Yee,
`Peter M. Howley, and Karl Manger
`
`Ronald F. Thomas, Brian D. Holt,
`Debra A. Schwinn,
`and Stephen B. Liggett
`P. Shaw, R. Bovey, S. Tardy, R. Sahli,
`B. Sordat, and J. Costa
`E. Ralf Sch6nbrunner and Franz
`X. Schmid
`
`H. Peter Spielmann, Srinivas S. Sastry,
`and John E. Hearst
`
`Keiko Kashiwagi, Saku Miyamoto,
`Fumihiro Suzuki, Hiroshi Kobayashi,
`and Kazuei Igarashi
`Walid Al-Feel,
`Subrahmanyam S. Chirala,
`and Salih J. Wakil
`
`Steven Ringquist
`and Cassandra L. Smith
`
`Koji Uchida and E, R, Stadtman
`
`Srikumar Chellappan, Virginia B. Kraus,
`Burkhard Kroger, Karl Munger,
`Peter M. Howley, William C. Phelps,
`and Joseph R. Nevins
`
`4221-4225
`
`4226-4230
`
`4231-4235
`4236-4239
`
`4275-4279
`
`4280-4284
`
`4295-4299
`
`4333-4337
`
`4368-4372
`
`4407-4411
`
`4437-44-41
`
`4442-4.4.16
`
`4490-4194
`
`4495-4499
`
`4510-45 13
`
`4514-4518
`
`4529-4533
`
`4534-4538
`
`4539-4543
`
`4544-4548
`
`4549-4553
`
`———|
`
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`

`

`Contents
`
`Modulation of the RNA-binding activity of a regulatory protein by iron in
`vitro: Switching between enzymatic and genetic function?
`
`Molecular cloning of epididymal and seminal vesicular transcripts encoding
`a semenogelin-related protein
`Amino acid substitutions in the sixth transmembrane domain of
`P-glycoprotein alter multidrug resistance
`Cleavage behavior of calicheamicin y' and calicheamicin T
`
`Endoproteolytic processing of a farnesylated peptide in vitro
`
`Expression cloning of a rat brain somatostatin receptor cDNA
`
`Polar zipper sequencein the high-affinity hemoglobin of Ascaris suum:
`Amino acid sequence andstructural interpretation
`
`Excision of Tn/O from the donorsite during transposition occurs byflush
`double-strand cleavages at the transposon termini
`Fatty acids activate a chimera of the clofibric acid-activated receptor and
`the glucocorticoid receptor
`Coupling of dual signaling pathways: Epidermal growth factor action
`involves the estrogen receptor
`
`In vitro replication of adeno-associated virus DNA
`Mutations in the catalytic subunit of cAMP-dependentprotein kinase result
`in unregulated biological activity
`Observing the 1H NMRsignal of the myoglobin Val-E11 in myocardium:
`An index of cellular oxygenation
`Mechanism of human methyl-directed DNA methyltransferase and the
`fidelity of cytosine methylation
`
`Behavior of a cloned murine interferon a/f receptor expressed in
`homospecific or heterospecific background
`
`An efficient method for generating proteins with altered enzymatic
`properties: Application to B-lactamase (Correction)
`Prohormone processing in Xenopus oocytes: Characterization of cleavage
`signals and cleavage enzymes (Correction)
`Molecular cloning of a calmodulin-dependent protein phosphatase from
`murinetestis: [dentification of a developmentally expressed nonneural
`isoenzyme (Correction)
`
`BIOPHYSICS
`
`Anne Constable, Sabine Quick,
`Nicola K. Gray, and
`Matthias W. Hentze
`
`HansLilja and Ake Lundwall
`
`Scott E. Devine, Victor Ling,
`and Peter W. Melera
`
`Suzanne Walker, Raphael Landovitz,
`Wei Dong Ding, George A. Ellestad,
`and Daniel Kahne
`
`Matthew N. Ashby, David S. King,
`and Jasper Rine
`Franz-Werner Kluxen, Christian Bruns,
`and Hermann Ltibbert
`
`Ivo De Baere, Lu Liu, Luc Moens,
`Jos Van Beeumen, Constant Gielens,
`Jean Richelle, Clive Trotman,
`John Finch, Mark Gerstein,
`and Max Perutz
`
`Howard W. Benjamin and
`Nancy Kleckner
`Martin Gottlicher, Eva Widmark, Qiao
`Li, and Jan-Ake Gustafsson
`Diane M. Jgnar-Trowbridge,
`Karen G. Nelson, Mark C. Bidwell,
`Sylvia W. Curtis, Todd F. Washburn,
`John A, McLachlan,
`and Kenneth S. Korach
`
`G. Hong, P. Ward, and K. I. Berns
`Stephanie A. Orellana
`and G. Stanley McKnight
`Ulrike Kreutzer, Dong S. Wang,
`and Thomas Jue
`
`Steven S. Smith, Bruce E. Kaplan,
`Lawrence C. Sowers,
`and Edward M. Newman
`
`Gilles Uzé, Georges Lutfalla,
`Marie-Thérése Bandu,
`Dominique Proudhon,
`and Knud E. Mogensen
`
`Arnold R. Oliphant and Kevin Struhl
`
`Judith Korner, Jay Chun, Laura
`O’Bryan, and Richard Axel
`Taro Muramatsu, Polavarapu Rathna
`Giri, Susumu Higuchi, and
`Randall L. Kincaid
`
`Complete 1SN and 1H NMRassignmentsfor the amino-terminal domain of
`the phage 434 repressor in the urea-unfolded form
`Environment affects amino acid preference for secondary structure
`
`Conformational switching at cytochrome a during steady-state turnover of
`cytochrome ¢ oxidase (Correction)
`
`Dario Neri, Gerhard Wider, and Kurt
`Wiithrich
`
`Lingxiu Zhong
`and W. Curtis Johnson, Jr.
`
`Robert A. Copeland
`
`CELL BIOLOGY
`
`Pasteurella multocida toxin is a potent inducer of anchorage-independent
`cell growth
`
`Theresa KE. Higgins, Anne C. Murphy,
`James M. Staddon, Alistair J. Lax,
`and Enrique Rozengurt
`
`4554-4558
`
`4559-4563
`
`4564-4568
`
`4608-4612
`
`4613-4617
`
`4618-4622
`
`4638-4642
`
`4648-4652
`
`4653-4657
`
`4658-4662
`
`4673-4677
`4726-4730
`
`4731-4733
`
`4744-4748
`
`4774-4778
`
`4779
`
`4779
`
`4779
`
`4397-4401
`
`4462-4465
`
`4779
`
`4240-4244
`
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`
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`

`

`Contents
`
`4245-4249
`
`4260-4264
`
`4290-4294
`
`4319-4323
`
`4338-4342
`
`4466-4470
`
`2 2
`
`4628~463
`4678-468
`
`4683-4687
`
`4688-4692
`
`4693~4697
`
`4734-4738
`
`+3 8
`
`4749-475
`4754-475
`
`Extension growth of the water mold Achlya: Interplay of turgor and
`wall strength
`Ontogeny of the secretory immune system: Maturation of a functional
`polymeric immunoglobulin receptor regulated by gene expression
`
`Nuclear translocation ofviral Jun but not of cellular Jun is cell
`cycle dependent
`Golgi retention of a trans-Golgi membrane protein, galactosyltransferase,
`requires cysteine and histidine residues within the membrane-
`anchoring domain
`
`SNCI, a yeast homolog of the synaptic vesicle-associated membrane
`protein/synaptobrevin gene family: Genetic interactions with the RAS
`and CAP genes
`Yeastactin filaments display ATP-dependentsliding movement over
`surfaces coated with rabbit muscle myosin
`Molecular diversity of L-type Ca?* channel transcripts in human fibroblasts
`Thymosin Bs (Fx peptide) is a potent regulator of actin polymerization in
`living cells
`
`Expression of interleukin 1-inducible genes and production of interleukin 1
`by aging humanfibroblasts
`Ja,25-Dihydroxyvitamin D3 regulates the transcription of carbonic
`anhydrase If mRNA in avian myelomonocytes
`Primary structure and expression of a gamete lytic enzyme in
`Chlamydomonasreinhardtii: Similarity of functional domains to
`matrix metalloproteases
`Endoplasmic reticulum resident protein of 90 kilodaltons associates with
`the T- and B-cell antigen receptors and major histocompatibility
`complex antigens during their assembly
`Proteins on exocytic vesicles mediate calcium-triggered fusion
`Tumornecrosis factor « is an autocrine growth regulator during
`macrophagedifferentiation
`
`Nicholas P. Money and Franklin
`M. Harold
`
`Sandra Huling, George R. Fournier,
`Anna Feren, Anan Chuntharapai,
`and Albert L. Jones
`
`Kazuhiro Chida and Peter K. Vogt
`
`Daisuke Aoki, Ni Lee, Naoto
`Yamaguchi, Craig Dubois,
`and Michiko N. Fukuda
`
`Jeffrey E. Gerst, Linda Rodgers,
`Michael Riggs, and Michael Wigler
`
`Stephen J. Kron, David G. Drubin,
`David Botstein, and James A. Spudich
`Nikolai M. Soldatov
`
`Mitchell C. Sanders, Allan L. Goldstein,
`and Yu-Li Wang
`S. Kumar, A. J. T. Millis,
`and C, Baglioni
`Abderrahim Lomri and Roland Baron
`
`Tetsu Kinoshita, Hideya Fukuzawa,
`Tomoo Shimada, Tatsuaki Saito,
`and Yoshihiro Matsuda
`
`Frans Hochstenbach, Violaine David,
`Simon Watkins,
`and Michael B. Brenner
`
`Steven S, Vogel and Joshua Zimmerberg
`Alice L. Witsell
`and Lawrence B. Schook
`
`DEVELOPMENTALBIOLOGY
`
`Production of germ-line chimeras in zebrafish by cell transplants from
`genetically pigmentedto albino embryos
`Id gene expression andits suppression by 1,25-dihydroxyvitamin D3 in rat
`osteoblastic osteosarcomacells
`Evidence that Mos protein may not act directly on cyclin
`
`Shuo Lin, Wilbur Long, Jin Chen,
`and Nancy Hopkins
`Nanako Kawaguchi, Hector F. DeLuca,
`and Masaki Noda
`
`Weilong Xu, Katherine J. Ladner,
`and L. Dennis Smith
`
`4519-4523
`
`4569-4572
`
`4573-4577
`
`GENETICS
`
`Leucine-responsive regulatory protein controls the expression of both the
`pap and fanpili operons in Escherichia coli
`
`Selection-induced mutations occur in yeast
`Two mutations in the B-globin polyadenylylation signal reveal extended
`transcripts and new RNA polyadenylylation sites
`
`Urate-nul! rosy mutants of Drosophila melanogaster are hypersensitive to
`oxygen stress
`Gencration of mice carrying a mutant apolipoprotein E gene inactivated by
`gene targeting in embryonic stem cells
`
`Organization and evolution of the human epidermal keratinocyte
`transglutaminase I gene
`
`Genetic identification of the DNA binding domain of Escherichia coli
`LexA protein
`Sequence organization of the Balbiani ring 2.1 gene in Chironomus tentans
`
`Vi
`
`Bruce A. Braaten, Jill V. Platko,
`Marjan W. van der Woude,
`Bert H. Simons, Frits K. de Graaf,
`Joseph M. Calvo, and David A. Low
`Barry G. Hall
`Deborah Rund, Caro] Dowling, Khamis
`Najjar, Eliezer A. Rachmilewitz, Haig
`H. Kazazian, Jr., and Ariella
`Oppenheim
`Arthur J. Hilliker, Brenda Duyf, David
`Evans, and John P. Phillips
`Jorge A. Piedrahita, Sunny H. Zhang,
`John R. Hagaman, Paula M. Oliver,
`and Nobuyo Maeda
`R. R. Polakowska, T. Eickbush,
`V. Falciano, F. Razvi,
`and L. A. Goldsmith
`Andrew T. Thliveris and David
`W. Mount
`Lars Wieslander and Gabrielle Paulsson
`
`4250-4254
`
`4300-4303
`4324-4328
`
`4343-4347
`
`4471-4475
`
`4476-4480
`
`4500-4504
`
`4578-4582
`
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`

`

`Contents
`
`Mutational spectrometry: A general approachfor hot-spot point mutations
`in selectable genes
`Dodecasatellite: A conserved G+C-rich satellite from the centromeric
`heterochromatin of Drosophila melanogaster
`
`Finding errors in DNA sequences
`
`IMMUNOLOGY
`
`Selective manipulation of the human T-cell receptor repertoire expressed
`by thymocytes in organ culture
`Humanization of an anti-p1854=R2 antibody for human cancer therapy
`
`Heat shock protein Hsp60-reactive é cells: A large, diversified
`T-lymphocyte subset with highly focused specificity
`
`Evidence for a functional receptor for cyclosporin A on the surface
`of lymphocytes
`
`Natural human antibodies to y interferon interfere with the
`immunomodulating activity of the lymphokine
`
`Human growth hormone promotes engraftment of murine or humanT cells
`in severe combined immunodeficient mice
`yé T-cell receptor repertoire in acute multiple sclerosis lesions
`
`A vaccine carrier derived from Neisseria meningitidis with mitogenic
`activity for lymphocytes
`
`How cytotoxic T cells manage to discriminate nonself from self at the
`nonapeptide level
`Quantitation of reversible binding by particle counting: Hapten-antibody
`interaction as a model system
`Characterization of a single-chain T-cell receptor expressed in
`Escherichia coli
`
`Phouthone Keohavong and
`William G. Thilly
`José P. Abad, Mar Carmena,
`Sigrid Baars, Robert D. C. Saunders,
`David M. Glover, Paloma Ludefia,
`Carlos Sentis, Chris Tyler-Smith,
`and Alfredo Villasante
`Janos Posfai and Richard J. Roberts
`
`Matthias Merkenschlager and Amanda
`G. Fisher
`
`Paul Carter, Len Presta, Cornelia M.
`Gorman, John B. B. Ridgway,
`Dennis Henner, Wai Lee T. Wong,
`Ann M. Rowland, Claire Kotts,
`Monique E. Carver,
`and H. Michael Shepard
`Rebecca L. O’Brien, Yang-Xin Fu,
`Robin Cranfill, Angela Dallas,
`Christina Ellis, Christopher Reardon,
`Julie Lang, Simon R. Carding,
`Ralph Kubo, and Willi Born
`Nicholas A. Cacalano, B.-X. Chen,
`W.Louis Cleveland,
`and Bernard F. Erlanger
`Adolfo Turano, Andrea Balsari,
`Elisabetta Viani, Santo Landolfo,
`Lorenzo Zanoni, Franco Gargiulo,
`and Arnaldo Caruso
`
`William J. Murphy, Scott K. Durum,
`and Dan L. Longo
`Kai W. Wucherpfennig, Jia Newcombe,
`Hong Li, Christine Keddy,
`M. Louise Cuzner,
`and David A. Hafler
`Margaret A. Liu, Arthur Friedman,
`Allen I. Oliff, Joseph Tai,
`Douglas Martinez, R. Randall Deck,
`Joseph T. C. Shieh,
`Timothy D. Jenkins, John J. Donnelly,
`and Linda A. Hawe
`Susumu Ohno
`
`Y. K. Sykulev, D. A. Sherman,
`R. J. Cohen, and H. N. Eisen
`William F. Soo Hoo, Michael J. Lacy,
`Lisa K. Denzin, Edward W. Voss, Jr.,
`Karl D. Hardman, and
`David M. Kranz
`
`4623-4627
`
`4663-4667
`
`4698-4702
`
`4255-4259
`
`4285-4289
`
`4348-4352
`
`4353-4357
`
`4447-4451
`
`4481-4485
`
`4588-4592
`
`4633-4637
`
`4643-4647
`
`4703-4707
`
`4759-4763
`
`MEDICAL SCIENCES
`
`Design of a long-acting follitropin agonist by fusing the C-terminal sequence
`of the chorionic gonadotropin 8 subunit to the follitropin 8 subunit
`
`Amplified and rearranged epidermal growth factor receptor genes in human
`gliobJastomas reveal deletions of sequences encoding portions of the N-
`and/or C-terminaltails
`Saturable binding of halothane to rat brain synaptosomes
`
`Immunostimulatory human urinary protein
`
`Fuad A. Fares, Nobuhiko Suganuma,
`Keiji Nishimori, Philip S. LaPolt,
`Aaron J. W. Hsueh, and Irving Boime
`A. Jonas Ekstrand, Noriaki Sugawa, C.
`David James, and V. Peter Collins
`
`Essam A. El-Maghrabi, Roderic G.
`Eckenhoff, and Henry Shuman
`Elisabeth Fontan, Héléne
`Saklani-Jusforgues, and Robert
`M. Fauve
`
`4304-4308
`
`4309-4313
`
`4329-4332
`
`4358-4362
`
`vii
`
`Pfizer Ex. 1008
`Page 7 of 14
`
`Pfizer Ex. 1008
`Page 7 of 14
`
`

`

`Contents
`
`2',5'-Bis-O-(tert-butyldimethylsilyl)-3'-spiro-5”-(4"-amino-1”,2’-oxathiole-2",
`2”-dioxide)pyrimidine (TSAO) nucleoside analogues: Highly selective
`inhibitors of human immunodeficiency virus type 1 that are targeted at
`the viral reverse transcriptase
`
`Germ-line mutations of the APC gene in 53 familial adenomatous
`polyposis patients
`
`Detection of acute hepatitis C virus infection by ELISA using a synthetic
`peptide comprising a structural epitope
`
`Surfactant-induced sealing of electropermeabilized skeletal muscle
`membranes in vivo
`
`Characterization of a type II collagen gene (COL2A/) mutation identified in
`cultured chondrocytes from human hypochondrogenesis
`
`Integration of gene maps: Chromosome 1
`
`Molecular cloning and characterization of the human cardiac Nat/Ca?t
`exchanger cDNA
`
`Jan Balzarini, Marfa-Jestis Pérez-Pérez,
`Ana San-Félix, Dominique Schols,
`Carlo-Federico Perno, Anne-Mieke
`Vandamme, Marfa-José Camarasa, and
`Erik De Clercq
`Yasuo Miyoshi, Hiroshi Ando, Hiroki
`Nagase, Isamu Nishisho, Akira Horii,
`Yoshio Miki, Takesada Mori, Joji
`Utsunomiya, Shozo Baba, Gloria
`Petersen, Stanley R. Hamilton,
`Kenneth W. Kinzler, Bert Vogelstein,
`and Yusuke Nakamura
`
`Girish J. Kotwal, Bahige M. Baroudy,
`1. Ken Kuramoto, Frances F.
`McDonald, Gilbert M. Schiff, Paul V.
`Holland, and Jerome B. Zeldis
`
`Raphael C. Lee, L. Philip River,
`Fu-shih Pan, Li Ji, and Robert
`L. Wollmann
`
`William A. Horton, Mirta A. Machado,
`Jeffrey Ellard, Dianna Campbell,
`James Bartley, Francesco Ramirez,
`Emilia Vitale, and Brendan Lee
`
`A. Collins, B. J. Keats, N. Dracopoli,
`D. C. Shields, and N. E. Morton
`
`[ssei Komuro, Kathleen E. Wenninger,
`Kenneth D. Philipson, and
`Seigo Izumo
`
`4392-4396
`
`4452-4456
`
`4486-4489
`
`4524-4528
`
`4583-4587
`
`4598-4602
`
`4769-4773
`
`MICROBIOLOGY
`
`Reduced transcription of the ferredoxin gene in metronidazole-resistant
`Trichomonas vaginalis
`
`Doris V. K. Quon, Christine E.
`d’Oliveira, and Patricia J. Johnson
`
`4402-4406
`
`NEUROBIOLOGY
`
`Three additional inositol 1,4,5-trisphosphate receptors: Molecular cloning
`and differential localization in brain and peripheral tissues
`
`Differential expression of c-Fos and Zif268 in rat striatum after haloperidol,
`clozapine, and amphetamine
`
`Developmentof antibodies against the rat brain somatostatin receptor
`
`Homosynaptic long-term depression in area CA] of hippocampusand
`effects of N-methyl-d-aspartate receptor blockade
`Immortal rat hippocampalcell lines exhibit neuronal and glial lineages and
`neurotrophin gene expression
`
`Primary structure of high molecular weight tau present in the peripheral
`nervous system
`
`A leucine-to-proline mutation in the putative first transmembrane domain of
`the 22-kDa peripheral myelin protein in the trembler-J] mouse
`
`Cloning ofthe rat gene encodingcholine acetyltransferase, a cholinergic
`neuron-specific marker
`Retinal degeneration is rescued in transgenic rd mice by expression of the
`cGMP phosphodiesterase 8 subunit
`
`Vill
`
`Christopher A. Ross, Sonye K. Danoff,
`Michael J. Schell, Solomon H. Snyder,
`and Axel Ulrich
`
`T. V. Nguyen, B. E. Kosofsky, R.
`Birnbaum, B. M. Cohen, and
`S. E. Hyman
`
`Magali Theveniau, Stephanie
`Rens-Domiano, Susan F. Law,
`Genevieve Rougon, and Terry Reisine
`Serena M. Dudek and Mark F. Bear
`
`Eva M. Eves, Marcy S. Tucker, John D.
`Roback, Martha Downen, Marsha Rich
`Rosner, and Bruce H. Wainer
`
`Dominique Couchie, Carmelo Mavilia,
`Irene S. Georgieff, Ronald K. H.
`Liem, Michael L. Shelanski, and
`Jacques Nunez
`Veli Suter, John J. Moskow,
`Andrew A. Welcher, G. Jackson
`Snipes, Bela Kosaras, Richard L.
`Sidman, Arthur M. Buchberg,
`and Eric M. Shooter
`
`Mounou Hahn, Soonjung L. Hahn,
`Donna M. Stone, and Tong H. Joh
`
`Janis Lem, John G. Flannery, Tiansen
`Li, Meredithe L. Applebury, Debora
`B. Farber, and Melvin I. Simon
`
`4265-4269
`
`4270-4274
`
`4314-4318
`
`4363-4367
`
`4373-4377
`
`4378-4381
`
`4382-4386
`
`4387-4391
`
`4422-4426
`
`Pfizer Ex. 1008
`Page 8 of 14
`
`Pfizer Ex. 1008
`Page 8 of 14
`
`

`

`Contents
`
`Evolution off the vasopressin/oxytocin superfamily: Characterization of a
`cDNA encoding a vasopressin-related precursor, preproconopressin,
`from the mollusc Lymnaea stagnalis
`
`Region-specific expression of a K* channel
`p
`
`g'
`
`genein brain
`
`Estrogen receptors colocalize with low-affinity nerve growth factor
`receptors in cholinergic neurons of the basal forebrain
`
`Actions of dopamine and dopaminergic drugs on cloned serotonin receptors
`expressed in Xenopus oocytes
`Neural-specific expression, genomic structure, and chromosomal
`localization of the gene encoding the zinc-finger transcription
`factor NGFI-C
`
`Oscillations in the insect brain: Do they correspondto the cortical y-waves
`of vertebrates?
`
`Ronald E. van Kesteren, August B.
`Smit, Roeland W. Dirks, Nico D. de
`With, Wijnand P. M. Geraerts,
`and Joos Joosse
`
`B. Rudy, C. Kentros, M. Weiser,
`D. Fruhling, P. Serodio,
`E. Vega-Saenz de Miera,
`M. H. Ellisman, J. A. Pollock,
`and H. Baker
`
`C. Dominique Toran-Allerand,
`Rajesh C. Miranda, Wayne D. L.
`Bentham, Farida Sohrabji, Theodore J.
`Brown, Richard B. Hochberg, and
`Neil J. MacLusky
`R. M. Woodward, M. M. Panicker,
`and R. Miledi
`
`Seth D. Crosby, Rosalie Ann Veile,
`Helen Donis-Keller, Jay M. Baraban,
`Ratan V. Bhat, Kelli S. Simburger,
`and Jeffrey Milbrandt
`K. Kirschfeld
`
`PHARMACOLOGY
`
`Demonstration of nuclear compartmentalization of glutathione
`in hepatocytes
`
`Giorgio Bellomo, Mariapia Vairetti,
`Lucianna Stivala, Francesca Mirabelli,
`Plinio Richelmi, and Sten Orrenius
`
`PHYSIOLOGY
`
`Modulation of L-type calcium channels by sodium ions
`
`C. William Balke and W. Gil Wier
`
`PLANT BIOLOGY
`Induction by fungalelicitor of S-adenosyl-L-methionine synthetase and
`S-adenosyl-L-homocysteine hydrolase mRNAs in cultured cells and
`leaves of Petroselinum crispum
`Light-induced phosphorylation of a membrane protein plays an early role in
`signal transduction for phototropism in Arabidopsis thaliana
`
`Petra Kawalleck, Gunnar Plesch, Klaus
`Hahibrock, and Imre E. Somssich
`
`Philippe Reymond, Timothy W. Short,
`Winslow R. Briggs, and Kenneth L.
`Poff
`
`POPULATION BIOLOGY
`Embryonic developmentperiod and the prevalence of avian blood parasites
`
`Robert E. Ricklefs
`
`4593-4597
`
`4603-4607
`
`4668-4672
`
`4708-4712
`
`4739-4743
`
`4764-4768
`
`4412-4416
`
`4417-4421
`
`4713-4117
`
`4718-4721
`
`4722-4725
`
`Pfizer Ex. 1008
`Page 9 of 14
`
`Pfizer Ex. 1008
`Page 9 of 14
`
`

`

`Proc. Natl. Acad, Sci. USA
`Vol. 89, pp. 4285-4289, May 1992
`Immunology
`
`Humanization of an anti-p185#"*? antibody for human
`cancer therapy
`(antibody engineering/site-directed mutagenesis/c-erbB-2 /neu)
`
`PAUL CARTER*, LEN PRESTA*, CORNELIA M. GorMANT, JOHN B. B. RIDGWAY‘, DENNIS HENNERT,
`Wat Lee T. Wonct, ANN M. Row.anp}, CLarre Kotts?, Monique E. Carver,
`AND H. MICHAEL SHEPARDS
`
`Departments of *Protein Engineering, tCell Genetics, {Medicinal and Analytical Chemistry, and §Cell Biology, Genentech Inc., 460 Point San Bruno
`Boulevard, South San Francisco, CA 94080
`
`Communicated by Hilary Koprowski, January 16, 1992 (received for review February 15, 1991)
`
`The murine monoclonalantibody mumAb4D5,
`ABSTRACT
`directed against human epidermal growth factor receptor 2
`(p185#=R2), specifically inhibits proliferation of human tumor
`cells overexpressing pI85¥FR?2_ However,
`the efficacy of
`mumAb4D5in human cancertherapyis likely to be limited by a
`humananti-mouse antibody response and lack of effector func-
`tions. A ‘“‘hamanized”’ antibody, humAb4D5-1, containing only
`the antigen binding loops from mumAb4D5 and humanvariable
`region framework residues plus IgG1 constant domains was
`constructed. Light- and heavy-chain variable regions were simul-
`taneously humanized in one step by ‘‘gene conversion mutagen-
`esis’ using 311-mer and 361-mer preassembled oligonucleotides,
`respectively. The humAb4D5-1 variant does not block the pro-
`Jiferation of human breast carcinoma SK-BR-3 cells, which
`overexpress p1854ER2, despite tight antigen binding (Ka = 25
`nM). One of seven additional humanized variants designed by
`molecular modeling (humAb4D5-8) binds the p185"=** antigen
`250-fold and 3-fold more tightly than humAb4D5-1 and
`mumAb4D5, respectively. In addition, humAb4D5-8 has potency
`comparable to the murine antibody in blocking SK-BR-3 cell
`proliferation. Furthermore, humAb4D5-8 is much moreefficient
`in supporting antibody-dependent cellular cytotoxicity against
`SK-BR-3 cells than mumAb4D5, but it does not efficiently kill
`WI-38 cells, which express p185"F®? at lower levels.
`
`The protooncogene HER2 encodes a protein tyrosine kinase
`(p1854ER?)
`that
`is homologous to the human epidermal
`growth factor receptor (1-3). Amplification and/or overex-
`pression of HER2 is associated with multiple human malig-
`nancies and appearsto beintegrally involved in progression
`of 25-30% of human breast and ovarian cancers (4, 5).
`Furthermore, the extent of amplification is inversely corre-
`lated with the observed median patient survival time (5). The
`murine monoclonal antibody mumAb4D5 (6), directed
`against the extracellular domain (ECD) of p185"®®, specif-
`ically inhibits the growth of tumorcell lines overexpressing
`pl85#2R2 in monolayer culture or in soft agar (7, 8).
`mumAb4D5 also has the potential of enhancing tumor cell
`sensitivity to tumor necrosis factor (7, 9). Thus, mumAb4D5
`has potential for clinical intervention in carcinomasinvolving
`the overexpression of p185#E®2,
`A major limitation in the clinical use of rodent mAbs is an
`anti-globulin response during therapy (10, 11). A partial
`solution to this problem is to construct chimeric antibodies by
`coupling the rodent antigen-binding variable (V) domains to
`human constant (C) domains (12-14). The isotype of the
`human C domains may be varied to tailor the chimeric
`antibody for participation in antibody-dependent cellular
`
`The publication costs ofthis article were defrayed in part by page charge
`payment. This article must therefore be hereby marked ‘‘advertisement”
`in accordance with 18 U.S.C. §1734 solely to indicate this fact.
`
`cytotoxicity (ADCC) and complement-dependent cytotoxic-
`ity (CDC) (15). Such chimeric antibody molecules arestill
`~30% rodent in sequence and are capable ofeliciting a
`significant anti-globulin response.
`Winter and coworkers (16-18) pioneered the ‘‘humaniza-
`tion’ of antibody V domains by transplanting the comple-
`mentarity determining regions (CDRs), which are the hyper-
`variable loops involved in antigen binding, from rodent
`antibodies into human V domains. The validity of this ap-
`proach is supported by the clinical efficacy of a humanized
`antibody specific for the CAMPATH-1 antigen with two
`non-Hodgkin lymphomapatients, one of whom had previ-
`ously developed an anti-globulin responseto the parental rat
`antibody (17, 19). In somecases, transplanting hypervariable
`loops from rodent antibodies into human frameworks is
`sufficient to transfer high antigen binding affinity (16, 18),
`whereasin other cases it has been necessary to also replace
`one (17) or sever