PMID- 28700571
OWN - NLM
STAT- MEDLINE
DCOM- 20171212
LR  - 20180112
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Linking)
VI  - 547
IP  - 7663
DP  - 2017 Jul 20
TI  - Open and closed structures reveal allostery and pliability in the HIV-1 envelope 
      spike.
PG  - 360-363
LID - 10.1038/nature23010 [doi]
AB  - For many enveloped viruses, binding to a receptor(s) on a host cell acts as the
      first step in a series of events culminating in fusion with the host cell
      membrane and transfer of genetic material for replication. The envelope
      glycoprotein (Env) trimer on the surface of HIV is responsible for receptor
      binding and fusion. Although Env can tolerate a high degree of mutation in five
      variable regions (V1-V5), and also at N-linked glycosylation sites that
      contribute roughly half the mass of Env, the functional sites for recognition of 
      receptor CD4 and co-receptor CXCR4/CCR5 are conserved and essential for viral
      fitness. Soluble SOSIP Env trimers are structural and antigenic mimics of the
      pre-fusion native, surface-presented Env, and are targets of broadly neutralizing
      antibodies. Thus, they are attractive immunogens for vaccine development. Here we
      present high-resolution cryo-electron microscopy structures of subtype B B41
      SOSIP Env trimers in complex with CD4 and antibody 17b, or with antibody b12, at 
      resolutions of 3.7 A and 3.6 A, respectively. We compare these to cryo-electron
      microscopy reconstructions of B41 SOSIP Env trimers with no ligand or in complex 
      with either CD4 or the CD4-binding-site antibody PGV04 at 5.6 A, 5.2 A and 7.4 A 
      resolution, respectively. Consequently, we present the most complete description 
      yet, to our knowledge, of the CD4-17b-induced intermediate and provide the
      molecular basis of the receptor-binding-induced conformational change required
      for HIV-1 entry into host cells. Both CD4 and b12 induce large, previously
      uncharacterized conformational rearrangements in the gp41 subunits, and the
      fusion peptide becomes buried in a newly formed pocket. These structures provide 
      key details on the biological function of the type I viral fusion machine from
      HIV-1 as well as new templates for inhibitor design.
FAU - Ozorowski, Gabriel
AU  - Ozorowski G
AD  - Department of Integrative Structural and Computational Biology, Center for
      HIV/AIDS Vaccine Immunology and Immunogen Discovery, International AIDS Vaccine
      Initiative Neutralizing Antibody Center, and Collaboration for AIDS Vaccine
      Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.
FAU - Pallesen, Jesper
AU  - Pallesen J
AD  - Department of Integrative Structural and Computational Biology, Center for
      HIV/AIDS Vaccine Immunology and Immunogen Discovery, International AIDS Vaccine
      Initiative Neutralizing Antibody Center, and Collaboration for AIDS Vaccine
      Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.
FAU - de Val, Natalia
AU  - de Val N
AD  - Department of Integrative Structural and Computational Biology, Center for
      HIV/AIDS Vaccine Immunology and Immunogen Discovery, International AIDS Vaccine
      Initiative Neutralizing Antibody Center, and Collaboration for AIDS Vaccine
      Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.
FAU - Lyumkis, Dmitry
AU  - Lyumkis D
AD  - Laboratory of Genetics and Helmsley Center for Genomic Medicine, The Salk
      Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla,
      California 92037, USA.
FAU - Cottrell, Christopher A
AU  - Cottrell CA
AD  - Department of Integrative Structural and Computational Biology, Center for
      HIV/AIDS Vaccine Immunology and Immunogen Discovery, International AIDS Vaccine
      Initiative Neutralizing Antibody Center, and Collaboration for AIDS Vaccine
      Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.
FAU - Torres, Jonathan L
AU  - Torres JL
AD  - Department of Integrative Structural and Computational Biology, Center for
      HIV/AIDS Vaccine Immunology and Immunogen Discovery, International AIDS Vaccine
      Initiative Neutralizing Antibody Center, and Collaboration for AIDS Vaccine
      Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.
FAU - Copps, Jeffrey
AU  - Copps J
AD  - Department of Integrative Structural and Computational Biology, Center for
      HIV/AIDS Vaccine Immunology and Immunogen Discovery, International AIDS Vaccine
      Initiative Neutralizing Antibody Center, and Collaboration for AIDS Vaccine
      Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.
FAU - Stanfield, Robyn L
AU  - Stanfield RL
AD  - Department of Integrative Structural and Computational Biology, Center for
      HIV/AIDS Vaccine Immunology and Immunogen Discovery, International AIDS Vaccine
      Initiative Neutralizing Antibody Center, and Collaboration for AIDS Vaccine
      Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.
FAU - Cupo, Albert
AU  - Cupo A
AD  - Department of Microbiology and Immunology, Weill Medical College of Cornell
      University, New York, New York, USA.
FAU - Pugach, Pavel
AU  - Pugach P
AD  - Department of Microbiology and Immunology, Weill Medical College of Cornell
      University, New York, New York, USA.
FAU - Moore, John P
AU  - Moore JP
AD  - Department of Microbiology and Immunology, Weill Medical College of Cornell
      University, New York, New York, USA.
FAU - Wilson, Ian A
AU  - Wilson IA
AD  - Department of Integrative Structural and Computational Biology, Center for
      HIV/AIDS Vaccine Immunology and Immunogen Discovery, International AIDS Vaccine
      Initiative Neutralizing Antibody Center, and Collaboration for AIDS Vaccine
      Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.
AD  - The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La
      Jolla, California 92037, USA.
FAU - Ward, Andrew B
AU  - Ward AB
AD  - Department of Integrative Structural and Computational Biology, Center for
      HIV/AIDS Vaccine Immunology and Immunogen Discovery, International AIDS Vaccine
      Initiative Neutralizing Antibody Center, and Collaboration for AIDS Vaccine
      Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.
LA  - eng
GR  - P01 AI110657/AI/NIAID NIH HHS/United States
GR  - P50 GM103368/GM/NIGMS NIH HHS/United States
GR  - R01 AI084817/AI/NIAID NIH HHS/United States
GR  - UM1 AI100663/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20170712
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Antibodies)
RN  - 0 (CCR5 protein, human)
RN  - 0 (CD4 Antigens)
RN  - 0 (HIV Envelope Protein gp41)
RN  - 0 (Immunoglobulin Fab Fragments)
RN  - 0 (Ligands)
RN  - 0 (Receptors, CCR5)
RN  - 0 (Receptors, HIV)
RN  - 0 (env Gene Products, Human Immunodeficiency Virus)
SB  - IM
MH  - *Allosteric Regulation/drug effects
MH  - Amino Acid Sequence
MH  - Antibodies/chemistry/immunology/pharmacology/ultrastructure
MH  - Binding Sites/drug effects
MH  - CD4 Antigens/chemistry/metabolism/ultrastructure
MH  - *Cryoelectron Microscopy
MH  - HIV Envelope Protein gp41/chemistry/genetics/metabolism/ultrastructure
MH  - HIV-1/*chemistry/*ultrastructure
MH  - Immunoglobulin Fab Fragments/chemistry/immunology/pharmacology/ultrastructure
MH  - Ligands
MH  - Models, Molecular
MH  - Receptors, CCR5/chemistry/metabolism
MH  - Receptors, HIV/chemistry/metabolism/ultrastructure
MH  - env Gene Products, Human Immunodeficiency
      Virus/chemistry/genetics/*metabolism/*ultrastructure
PMC - PMC5538736
MID - NIHMS878809
EDAT- 2017/07/13 06:00
MHDA- 2017/12/13 06:00
CRDT- 2017/07/13 06:00
PHST- 2016/11/17 00:00 [received]
PHST- 2017/05/22 00:00 [accepted]
PHST- 2017/07/13 06:00 [pubmed]
PHST- 2017/12/13 06:00 [medline]
PHST- 2017/07/13 06:00 [entrez]
AID - nature23010 [pii]
AID - 10.1038/nature23010 [doi]
PST - ppublish
SO  - Nature. 2017 Jul 20;547(7663):360-363. doi: 10.1038/nature23010. Epub 2017 Jul
      12.