最新《细胞》发布细胞信号重要成果

【字体: 时间:2008年01月28日 来源:生物通

编辑推荐:

  来自斯坦福大学医学院分子与细胞生理学系,霍德华休斯医学院,马里兰大学医学院微生物与免疫学系,血管及炎症疾病研究中心的研究人员对白细胞介素4(interleukin-4,IL-4)和白细胞介素13(interleukin-3,IL-13)细胞因子进行了描述,发现了其一套完整的受体结合因子,这对于进一步了解细胞信号传导,特别对于解开为什么相似受体的结合能进行特异性的信号传导这一谜团意义重大。这一研究成果公布在最新一期(01月25日)《Cell》杂志,并且作为封面文章。

  

生物通报道:来自斯坦福大学医学院分子与细胞生理学系(Departments of Molecular and Cellular Physiology,生物通注),霍德华休斯医学院,马里兰大学医学院微生物与免疫学系,血管及炎症疾病研究中心(Center for Vascular and Inflammatory Diseases)的研究人员对白细胞介素4(interleukin-4,IL-4)和白细胞介素13(interleukin-3,IL-13)细胞因子进行了描述,发现了其一套完整的受体结合因子,这对于进一步了解细胞信号传导,特别对于解开为什么相似受体的结合能进行特异性的信号传导这一谜团意义重大。这一研究成果公布在最新一期(01月25日)《Cell》杂志,并且作为封面文章。


(《Cell》封面: IL-4/IL-4Ra复合物利用“蓝线条”形成I类复合物,利用“红线条”形成II类复合物)

 

领导这一研究的是斯坦福大学医学院的K. Christopher Garcia教授,主要从事蛋白晶体结构领域的研究,去年7月,Garcia实验室解开了T细胞受体如何识别自己和外源的主要组织兼容性复合体MHC的秘密——MHC是脊椎动物体内,与免疫反应调节有关的一个基因家族。研究人员通过解析2C TCR与它的外源配基H-2Ld-Q配体的结构惊讶地发现,这种TCR利用一种不同寻常的策略,使用外源的pMHC。

 

在这篇最新的文章中主要围绕着白细胞介素IL-4/IL-13系统进行,白细胞介素是由多种细胞产生并作用于多种细胞的一类细胞因子,由于最初是由白细胞产生又在白细胞间发挥作用,所以由此得名。

 

白细胞介素共有29个,分别命名为IL-1---IL29,功能复杂,形成网络,复杂重叠。其中白细胞介素4(IL-4)主要由Th2细胞、肥大细胞及嗜碱性粒细胞产生,主要作用是促B细胞增殖、分化;诱导IgG1 和IgE产生;促进Th0细胞向Th2细胞分化;抑制Th1细胞活化及分泌细胞因子;协同IL-3刺激肥大细胞增殖等。而白细胞介素13(IL-13)是一种多功能的免疫调节性细胞因子,主要由活化T淋巴细胞分泌产生。

 

这两种因子对于T细胞介导的体液免疫应答具有重要的意义,能通过与不同的受体结合行使功能。在这篇文章中,研究人员获得了三种细胞因子-受体三聚体的结晶结构,为更加深入理解这些细胞因子即使是结合了相似的受体复合物,但是具有特异性的信号功能这一谜团提供了重要信息。

 

虽然说不同的配基在相同受体上能开启不同的信号流这一生物现象并不少见,但是在这一研究中,结晶结构揭示出相同的受体能识别出仅仅存在细微差别的配基,比如IL4和IL-13。这IL4和IL-13共享的受体实际上是两个受体的复合体: IL-4 receptor α和the IL-13 receptor α,两者都需要启动一个信号,但是IL-4首先接触到IL-4受体,并且亲和度很高,IL-13也是首次触到IL-13受体,研究人员认为这种结合顺序上的细微差别,以及启动信号途径的亲和性会产生相互对抗作用。

 

这一研究的重要意义在于揭示了受体复合物在应答每一种细胞因子的时候具有不同的集合特征,以及信号能力,说明细胞因子-受体细胞外的相互作用受到细胞内细胞近膜端(membrane proximal)信号的调控。

 

大部分的配基都是通过将受体元件聚集到细胞表面进行工作,对于许多受体而言,这足以启动一个信号,这项研究表明启动一个信号途径不仅仅依赖于激活受体,也需要运动上的复杂差异,以及受体细胞表面的结合。

 

由于IL-4和IL-13启动了对于一些像是过敏或者哮喘之类疾病中的重要的信号途径,因此这一研究对于药物研发设计而言也具有十分重要的意义,对于这些特殊顺序的了解也许将有助于开发出模拟一个信号与另一相对抗信号的药物设计分子。
(生物通:张迪)

 

原文摘要:
Copyright © 2008 Cell Press. All rights reserved.
Cell, Vol 132, 259-272, 25 January 2008
Molecular and Structural Basis of Cytokine Receptor Pleiotropy in the Interleukin-4/13 System


 

名词解释:

 

1.白细胞介素interleukin

 

白细胞介素是由多种细胞产生并作用于多种细胞的一类细胞因子。由于最初是由白细胞产生又在白细胞间发挥作用,所以由此得名,现仍一直沿用。


缩写为IL。关于免疫反应的表达和调节,有来源于淋巴细胞或巨噬细胞等许多因子参与。来源于淋巴细胞的有淋巴细胞活素,来源于巨噬细胞的总称为monokine,其中的各个因子的生物活性各有不同(例如巨噬细胞活化,促进T细胞繁殖等),因子自身的物理化学性质多不清楚。1979年这方面的研究团体提出了在淋巴细胞活素及巨噬细胞因子(monoki-ne)中,已作为一种分子提纯并弄清了性质的称为白细胞间[杀菌]素。最初测定的为 IL1和IL2。IL1属于monokine,以前曾以淋巴细胞活化因子(lymphocyte activating factor)。细胞促进蛋白质(mitogenic protein)以及B细胞活化因子(B cell-activating factor)等七种名称称之。而IL2属于淋巴细胞活素,以前曾以胸腺细胞刺激因子(thymocyte stimulating factor)、 T细胞生长因子(T cell growth factor)等六种名称称之。



最初是指由白细胞产生又在白细胞间起调节作用的细胞因子。
现在是指一类分子结构和生物学功能已基本明确,具有重要调节作用而统一命名的细胞因子
目前发现了29个白细胞介素,分别命名为IL-1---IL29.功能复杂,成网络,复杂重叠。

 

附:美国蛋白结晶结构研究的主流实验室(转载)

 

来美国学习做蛋白结构第5年了。鉴于这个领域目前在CNS上的灌水量,一大批的大牛,小牛们如雨后春笋般涌现了出来。为了对这个领域有一个宏观的把握,我根据自己的印象罗列了下面一个在美国做X-ray crystallography的超级大牛的list (按照first name为序,排名不分先后)。限于本人的知识面和阅历有限,下面这个list难免管中窥豹,挂一漏万;希望方家们多多斧正,多多赐教。得到feedback后,我将完善这个list,做成完整版,以飨后人。



Name list:
Ann Stock @ Rutgers,
Brian K. Kobilka @ Stanford,
Brian W. Matthews @ University of Oregon,
Brunger, Axel T @ Stanford,
Christopher K. Garcia @ Stanford,
Cynthia Wolberger @ Johns Hopkins,
David A. Agard @ UCSF,
David Eisenberg @ UCLA,
Douglas C. Rees @ Caltech,
Eric,Gouaux @ Vollum Institute,
Gregory A. Petsko & Dagmar Ringe (Petsko’s wife) @ Brandeis,
Günter Blobel @ Rockefeller University,
Ian A. Wilson @ Scripps,
James H. Hurley @ NIDDK,
Jennifer A. Doudna @ Berkeley,
Johann Deisenhofer @ UT Southwestern Medical Center,
Jonathan Goldberg @ Memorial Sloan-Kettering Cancer
John Kuriyan @ UC Berkeley,
John York @ Duke,
Karolin Luger @ Colorado State University,
Michael G. Rossmann @ Purdue,
Nikola Pavletich @ Memorial Sloan-Kettering Cancer Center,
Peter B. Moore@ Yale,
Pamela Bjorkman @ Caltech,
Raymond C. Stevens @ Scripps,
Robert Stroud @ UCSF,
Roderick MacKinnon @ Rockefeller,
Roger Kornberg @ Stanford,
Stephen C. Harrison @ Harvard,
Susan S. Taylor @ UCSD,
Thomas R. Cech @ University of Colorado at Boulder,
Thomas A. Steitz @ Yale,
Wayne A. Hendrickson @ Columbia,
William N. Zagotta @ University of Washington,
Yigong Shi @ Princeton

1. Ann Stock @ Rutgers, Title: Professor, HHMI Investigator. Gregory A.
Petsko’s post-doc.
a) Molecular mechanisms of receptor-mediated signal transduction composed
of a small number of components: a family of transmembrane receptor
proteins, two receptor modifying enzymes, the flagellar motor apparatus, and
four cytoplasmic signal transduction proteins that function in a
phosphotransfer pathway that links receptor signaling to the motor response.
b) "Two-component" proteins involved in phosphotransfer signaling systems
: transfer of a high energy phosphoryl group from a histidine protein kinase
to an aspartyl residue of a response regulator.
c) Niemann-Pick disease type C2 (NP-C2): a soluble lysosomal cholesterol-
binding protein

2. Brian K. Kobilka @ Stanford, Title: Professor.
a) 4 high impact factor journal paper in 2007 on the crystal structure of
the human beta 2 adrenergic G protein coupled receptor. A potential Nobel
Laureate winner.

3. Brian W. Matthews @ University of Oregon, Title: Professor, HHMI
Investigator. The famous Matthews’ coefficient was proposed by this guy.
Ted Baker, James H. Hurley, Allen Orville used to work with him.
a) Protein Folding, Stability, and Design using T4 lysozyme system.
b) structural basis of DNA-protein recognition, cro repressor protein
from bacteriophage lambda , and a cro-operator complex
c) Structure and function of peptidases including the thermostable zinc
protease thermolysin, the cobalt-requiring methionine aminopeptidase from E.
coli as well as the serine peptidases.
d) Escherichia coli beta-galactosidase, one of the classic enzymes in
molecular biology.
e) Are nonpolar Cavities in Proteins Empty? High-pressure crystallography
suggests nonpolar cavities in proteins are empty unless they are
sufficiently large to accommodate three or more water molecules that can
hydrogen-bond to each other.

4. Brunger, Axel T @ Stanford, Title: Professor, HHMI Investigator.
Author of CNS. Gregory A. Petsko’s post-doc.
a) Synaptic Vesicle Fusion: the synaptic SNARE complex, consisting of
syntaxin, synaptobrevin, and SNAP-25
b) Mechanism of Action of Clostridial Neurotoxins: Clostridial
neurotoxins (CNTs), such as botulinum (BoNT) and tetanus (TeNT) neurotoxins
impair neuronal exocytosis by specific proteolysis of SNARE proteins once
inside the neuron. High specificity revealed by the receptor-binding domain
of botulinum neurotoxin serotype B (BoNT/B) bound to the luminal domain of
synaptotagmin II, while enzyme activity revealed by a CNT endopeptidase in
complex with its target SNARE
c) AAA ATPases: Fusion of opposing membranes results in the formation of
cis-SNARE complexes that are disassembled for recycling and reactivation by
the joint action of SNAP and NSF (a hexameric AAA). They also pursue
structural and functional studies of p97 (also called VCP, valosin-
containing protein; VAT in Archaebacteria; and cdc48 in yeast), a distant
homolog of NSF
d) Sec6/8 Complex: The tethering complex for exocytosis at the plasma
membrane is referred to as the sec6/8 complex, or exocyst, in yeast.
e) Endocytosis: Synaptic vesicle membrane that fuses with the plasma
membrane is recycled via clathrin-mediated exocytosis.
f) Small G proteins: Small G proteins and their effectors involved in
vesicle trafficking

5. Christopher K. Garcia @ Stanford, Title: Professor, HHMI Investigator.
Ian A. Wilson’s post-doc.
a) Immune recognition & signaling: T cell receptor recognition of peptide
-MHC. Innate immune receptors - ligand recognition and signaling. Energetics
of T cell recognition - specificity versus degeneracy. Understanding the
role of the CD3 signaling components in associating with the T cell receptor
. Structure and function of the pre-B and pre-T cell antigen receptors. TCR
recognition of ligand.
b) Host-pathogen interactions. Understanding the recognition of microbial
ligands by mammalian host receptors. Molecular mimicry in microbial
pathogenesis. Molecular basis for bacterial enterotoxin induction of
diarrheal disease.
c) Neural and Vasoactive hormone receptors. Neuronal regeneration
receptors such as Nogo and their interactions with ligand. Neurotrophic
factors (Nerve Growth Factor, Glial-derived neurotrophic factor, CNTF).
Natriuretic peptide (ANP) receptor recognition and allosteric activation
mechanism.
d) Cytokines and shared signaling receptors. Molecular basis of higher-
order assembly, and ligand recognition by the shared signaling receptor
gp130. Structural aspects of intracellular signaling by cytokine receptors (
e.g. JAK/STAT)

6. Cynthia Wolberger @ Johns Hopkins, Title: Associate Professor, HHMI
Associate Investigator. Robert Stroud’s post-doc.
a) Transcriptional Silencing: Sir2, an enzyme that deacetylates lysine
side chains in an unusual reaction that requires NAD+.
b) Assembly of Lys63-Linked Polyubiquitin Chains: Polyubiquitin chains
with different types of lysine linkages play distinct biological roles such
as destruction by the proteasome for Lys48-linked polyubiquitin or
nondegradative signals at Lys63 position.

7. David A. Agard @ UCSF, Title: Professor, HHMI Investigator.
a) Molecular mechanisms of agonism and antagonism for the Estrogen
Receptor
b) Structural and functional analysis of Hsp90

8. David Eisenberg @ UCLA, Title: Professor, HHMI Investigator, Member of
National Academy of Sciences. Former postdoctoral fellows include Chris
Hill, Tom Terwilliger.
a) Amyloids and prions, pathologically interacting proteins.
b) The structural biology of Mycobacterium tuberculosis, as part of the
TB Structural Genomics Consortium.

9. Douglas C. Rees @ Caltech, Title: Professor, HHMI Investigator.
a) Metalloproteins: Unusual molybdenum and tungsten containing centers,
including the FeMo-cofactor of nitrogenase and the more widespread
molybdenum cofactor that participate in many of the basic reactions of the
biological nitrogen and sulfur cycles.
b) Membrane Proteins: ATP Binding Cassette (ABC) transporters that
utilize the binding and hydrolysis of ATP to translocate ligands across the
membrane. Prokaryotic mechanosensitive channels (Msc), including those of
large (MscL) and small (MscS) conductance that couple channel gating with
membrane tension.

10. Eric Gouaux @ Vollum Institute, Title: Professor, HHMI Investigator.
One of the best membrane crystallographer in the world, second to nobody.
a) Eukaryotic glutamate receptors and bacterial homologs of the
transporters for glutamate, glycine and the biogenic amines.
b) Acid-sensing ion channel 1.

11. Gregory A. Petsko & Dagmar Ringe (Petsko’s wife) @ Brandeis, Title:
Gyula and Katica Tauber Professor, HHMI Investigator. Former graduate
student/postdoctoral fellow include John Kuriyan/Brunger Axel T and Ann
Stock. A benchmark kind of guy. Enough said.
a) Bridged Bimetallic Enzymes.
b) Proteins involved in cancer that modify other proteins.
c) Mechanisms of Enzymatic Hydrogen Ion Transfer.
d) Pyridoxal Phosphate (Vitamin B6).
e) Control of Transcription in Prokaryotes by Metal- dependent repressors.

12. Günter Blobel @ Rockefeller University, Title: John D. Rockefeller,
Jr. Professor, HHMI Investigator. 1999 Nobel Laureate in Physiology or
Medicine for the discovery that proteins have intrinsic signals that govern
their transport and localization in the cell.
a) Their laboratory has contributed to understanding of the composition
of the NPC, its structure, and the traffic across it.
b) They have isolated the first proteins of the NPC and termed them
collectively nucleoporins (nups).
c) Structure of Nup58/45 suggests flexible nuclear pore diameter by
intermolecular sliding

13. Ian A. Wilson @ Scripps, Title: Professor. PI of the Administrative
Core of Joint Center for Structural Genomics (JCSG), a member of NIH Protein
Structure Initiative - Phase II (PSI II). Christopher Garcia, Mingdong
Huang and Caroline Wilmot used to work with him.
a) Immune Recognition: To understand the interaction of foreign antigens
with the immune system through high-resolution x-ray structural studies of
antibodies and antigens in the humoral system, T-cell receptor complexes
with MHC class I and class II in the cellular system, and through pattern
recognition receptors in the innate immune system.
b) Viral Pathogens: The 1918 flu, which killed 20-40 million people
worldwide, is being reinvestigated through structural studies of the 1918
viral proteins, such as the hemagglutinin and neuraminidase.
c) Anticancer Targets: Inhibitors of glycinamide ribonucleotide
transformylase and ATIC enzymes that catalyze the enzymatic steps that
require reduced folate cofactors in the purine biosynthetic pathway. These
enzymes represent novel targets for antineoplastic intervention.

14. James H. Hurley @ NIDDK, Title: NIH Senior Investigator, Section
Chief on Structural Biology and Cell Signaling, LMB, NIDDK. PhD training
with Robert Stroud, Postdoctoral training with Brian Matthews & Jim
Remington.
a) Large multiprotein complexes and on understanding the roles of
ubiquitin, phosphoinositides, diacylglycerol, and cholesterol in signaling
and trafficking

15. Jennifer A. Doudna @ Berkeley, Title: Professor, HHMI Investigator,
Member of National Academy of Sciences, Fellow of American Academy of Arts
and Sciences. Visiting scientist training with Thomas R. Cech
a) Internal Ribosome Entry Site (IRES) RNAs.
b) Structure and Mechanism of the Signal Recognition Particle (SRP).
c) RNA Recognition by Dicer Enzymes.

16. Johann Deisenhofer @ UT Southwestern Medical Center, Title: Virginia
and Edward Linthicum Distinguished Chair in Biomolecular Science Regental
Professor, HHMI Investigator, Member of National Academy of Sciences, Member
of Academia Europaea. 1999 Nobel Laureate in Chemistry for the
determination of the three-dimensional structure of a photosynthetic
reaction centre.
a) Structural Biology of Cholesterol Homeostasis: human LDL receptor,
membrane-bound portions of the proteins HMG-CoA reductase and SCAP, which
show sequence similarity in five membrane-spanning segments; this and their
interaction with the protein INSIG suggest a common mechanism for
cholesterol sensing
b) Innate Immunity of Insects: Peptidoglycan-recognition proteins (PGRPs)
from Drosophila, which bind components of bacterial cell walls and activate
signaling pathways that lead to the synthesis of antimicrobial peptides.
The thioester-containing protein TEP1r from the malaria vector Anopheles
gambiae. This protein of about 1,300 amino acids is homologous to the human
complement protein C3.
c) Iron transporters from the outer membrane of gram-negative bacteria,
the light activated DNA repair enzyme photolyase in a complex with a
substrate, photolyase-related blue light photorecptors, the neural proteins
synapsin and neurexin 1, the mitochondrial processing peptidase from yeast

17. Jonathan Goldberg @ Memorial Sloan-Kettering Cancer Center, Title:
HHMI Investigator. John Kuriyan’s post-doc.
a) Activation of ARF GTPases: The mechanism by which ARF-family GTPases
are activated to the GTP-bound state by exchange factors was revealed by the
crystal structure of ARF1 complexed with a cognate exchange factor of the
Sec7 family.
b) Mechanism of GTP-myristoyl Switching: The binding of GTP to ARF1
triggers the exposure of its myristoylated N terminus, causing it to
translocate from cytosol to the membrane surface.
c) GTP Hydrolysis and Cargo Sorting Mechanisms: During vesicle budding,
GTP hydrolysis on ARF1 acts negatively to release coat proteins from
membranes, and this may impose kinetic restraints on the selection of cargo
molecules into vesicles.

18. John Kuriyan @ UC Berkeley, Title: Chancellor's Professor, HHMI
Investigator. Jonathan Goldberg used to work with him.
a) Regulation of the Src and Abl tyrosine kinases: autoinhibition of c-
Src and c-Abl.
b) The inhibition of the Abl tyrosine kinase by imatinib (Gleevec).
c) Activation of Ras by nucleotide exchange.
d) Autoregulation of Ca2+/calmodulin-dependent protein kinase II.
e) Autoinhibition and activation mechanisms of EGFR.
f) Processive DNA Replication.

19. John York @ Duke, Title: Associate Professor, HHMI Investigator.
a) Nuclear Inositol Signaling.
b) Phosphatase Regulation of Inositol Lipid Messengers.
c) Lithium Pharmacology.

20. Karolin Luger @ Colorado State University, Title: CSU Distinguished
Professor, HHMI Investigator.
a) Histone Variants.
b) Interaction of Nucleosomes with Small Synthetic Molecules and with
Transcription Factors.
c) Nucleosome Assembly and Histone Exchange.

21. Michael G. Rossmann @ Purdue, Title: Hanley Professor, Member of the
National Academy of Sciences, Fellow of the American Academy of Arts and
Sciences. The famous Rossmann fold is named after him. McPherson Alexander J
. Jr, Tong Liang used to work with him.
a) Alpha Viruses, Bacteriophages, Flavivirus, MimiVirus, Parvo Viruses,
PBCV-1, Picorna Viruses, RNA polymerase.

22. Nikola Pavletich @ Memorial Sloan-Kettering Cancer Center, Title:
HHMI Investigator.
a) Function of BRCA2 in DNA Repair.
b) Control of the G1-S Transition by the Retinoblastoma Protein.

23. Peter B. Moore@ Yale, Title: Professor, HHMI Investigator, Member of
National Academy of Sciences, Fellow of American Academy of Arts and
Sciences.
a) Determine the structural consequences of mutations in both rRNA and in
ribosomal proteins in the large ribosomal subunit.
b) Study the translational control of ribosomal protein synthesis in
bacteria using NMR, crystallography and molecular biology as tools.
c) Characteriz the complexes that form between snoRNAs and rRNA
precursors in the nucleoli of mammalian cells.

24. Pamela Bjorkman @ Caltech, Title: Max Delbrück Professor, HHMI
Investigator. Andrew Herr, Xiao-Dong Su used to work with her.
a) Homologs and mimics of class I MHC proteins.

25. Raymond C. Stevens @ Scripps, Title: Professor.
a) Considered of the fathers of high-throughput x-ray crystallography. In
October, 2007, Stevens published the first structure of human β2-
adrenergic receptor–T4 lysozyme fusion protein in collaboration Brian K.
Kobilka.

26. Robert Stroud @ UCSF, Title: Professor, Member of the National
Academy of Sciences. Former graduate student/postdoctoral fellow include
David A. Agard, Jim Hurley/ Cynthia Wolberger.
a) Ammonia channel, aquaporins, signal recognition particle (SRP),
glycerol channel, polyketide synthase, RNA processing enzymes, HIV integrase
, HIV protease, KSHV protease, pro-chymase protease, erythropoietin receptor
, bacteriorhodopsin, cholesterol esterase, colicin, acetylcholine receptor,

27. Roderick MacKinnon @ Rockefeller, Title: John D. Rockefeller, Jr.
Professor, HHMI Investigator, Member of the National Academy of Sciences.
2003 Nobel Laureate in Chemistry for structural and mechanistic studies of
ion channels.
a) Structure and function of ion channels and associated regulatory
proteins.

28. Roger Kornberg @ Stanford, Title: Professor, Member of National
Academy of Sciences, Fellow of American Academy of Arts and Sciences. 2006
Nobel Laureate in Chemistry for his studies of the molecular basis of
eukaryotic transcription.
a) RNA polymerase II.

29. Stephen C. Harrison @ Harvard, Title: Professor, HHMI Investigator,
Member of the National Academy of Sciences, Fellow of the American Academy
of Arts and Sciences, Member of the American Philosophical Society. His name
equals to virus protein crystallography in the field.
a) The structure, assembly, and cell-entry properties of virus particles.
b) The structural basis for integration of diverse molecular signals,
both in transmission of information from the cell membrane to the nucleus
and in regulating gene expression.
c) The molecular machinery for various transport steps in membrane
traffic.
d) The molecular organization of kinetochores.

30. Susan S. Taylor @ UCSD, Title: Professor, HHMI Investigator.
a) cAMP-dependent Protein Kinase.

31. Thomas R. Cech @ University of Colorado at Boulder, Title: Professor,
HHMI President, Member of National Academy of Sciences. 1989 Nobel Laureate
in Chemistry for their discovery of catalytic properties of RNA. Former
postdoctoral fellow include Anna Marie Pyle, Jennifer A. Doudna.
a) X-Ray Crystallography of RNA
b) Replication of Chromosome Ends by Telomerase: telomerase reverse
transcriptases (TERTs), distant relatives of the enzyme responsible for
copying the RNA of the human immunodeficiency virus, HIV.
c) The Protein That Caps the Chromosome End: heterodimeric telomere end-
binding protein (TEBP)

32. Thomas A. Steitz @ Yale, Title: Sterling Professor, HHMI Investigator
, Member of National Academy of Sciences, Fellow of American Academy of Arts
and Sciences.
a) DNA replication: the atomic structure of the 50S ribosomal subunit and
its complexes with substrate, intermediate and product analogues as well as
complexes with more than a dozen antibiotics.
b) Transcription: six structures of T7 RNA polymerase captured in various
functional states show the structural basis of the transition from the
initiation to elongation phase.
c) Translation: The structures of the CCA-adding enzyme captured in each
state of CCA incorporation onto tRNA explain the enzyme's specificity for
nucleotide incorporation in the absence of a nucleic acid template.
d) Genetic recombination: The structure of a recombination intermediate
of γδ resolvase suggests that site specific recombination by this enzyme
is achieved by subunit rotation.

33. Wayne A. Hendrickson @ Columbia, Title: Professor, HHMI Investigator,
Member of National Academy of Sciences.
a) Structure of Core gp120
b) CD4-Receptor Interface
c) Antibody and Chemokine-Receptor Interface
d) Model of Trimeric Structure
e) Energetics of gp120-CD4 Binding
f) Evasion of Immune Responses
g) Mechanism of Cell Invasion

34. William N. Zagotta @ University of Washington, Title: Professor, HHMI
Investigator.
a) Cyclic nucleotide–gated (CNG) channels, hyperpolarization-activated
cyclic nucleotide–modulated (HCN) channels.

35. Yigong Shi @ Princeton, Title: Warner-Lambert/Parke-Davis Professor.

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