title: An atomic model of HIV-1 capsid-SP1 reveals structures regulating assembly and maturation.
abstract: Immature HIV-1 assembles at and buds from the plasma membrane before proteolytic cleavage of the viral Gag polyprotein induces structural maturation. Maturation can be blocked by maturation inhibitors (MIs), thereby abolishing infectivity. The CA (capsid) and SP1 (spacer peptide 1) region of Gag is the key regulator of assembly and maturation and is the target of MIs. We applied optimized cryo-electron tomography and subtomogram averaging to resolve this region within assembled immature HIV-1 particles at 3.9 angstrom resolution and built an atomic model. The structure reveals a network of intra- and intermolecular interactions mediating immature HIV-1 assembly. The proteolytic cleavage site between CA and SP1 is inaccessible to protease. We suggest that MIs prevent CA-SP1 cleavage by stabilizing the structure, and MI resistance develops by destabilizing CA-SP1.
authors.affiliation: Structural and Computational Biology Unit, European Molecular Biology Laboratory, Meyerhofstraße 1, 69117 Heidelberg, Germany. Molecular Medicine Partnership Unit, European Molecular Biology Laboratory-Universitätsklinikum Heidelberg, Heidelberg, Germany.
authors.forename: Florian K M
authors.initials: FK
authors.lastname: Schur
authors.affiliation: Molecular Medicine Partnership Unit, European Molecular Biology Laboratory-Universitätsklinikum Heidelberg, Heidelberg, Germany. Department of Infectious Diseases, Virology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Obr
authors.affiliation: Structural and Computational Biology Unit, European Molecular Biology Laboratory, Meyerhofstraße 1, 69117 Heidelberg, Germany.
authors.forename: Wim J H
authors.initials: WJ
authors.lastname: Hagen
authors.affiliation: Structural and Computational Biology Unit, European Molecular Biology Laboratory, Meyerhofstraße 1, 69117 Heidelberg, Germany.
authors.forename: William
authors.initials: W
authors.lastname: Wan
authors.affiliation: Structural and Computational Biology Unit, European Molecular Biology Laboratory, Meyerhofstraße 1, 69117 Heidelberg, Germany. Hamburg Unit c/o DESY (Deutsches Elektronen-Synchrotron), European Molecular Biology Laboratory, Notkestraße 85, 22607 Hamburg, Germany.
authors.forename: Arjen J
authors.initials: AJ
authors.lastname: Jakobi
authors.affiliation: Proteomics Core Facility, European Molecular Biology Laboratory, Meyerhofstraße 1, 69117 Heidelberg, Germany.
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Kirkpatrick
authors.affiliation: Structural and Computational Biology Unit, European Molecular Biology Laboratory, Meyerhofstraße 1, 69117 Heidelberg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Sachse
authors.affiliation: Molecular Medicine Partnership Unit, European Molecular Biology Laboratory-Universitätsklinikum Heidelberg, Heidelberg, Germany. Department of Infectious Diseases, Virology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Kräusslich
authors.affiliation: Structural and Computational Biology Unit, European Molecular Biology Laboratory, Meyerhofstraße 1, 69117 Heidelberg, Germany. Molecular Medicine Partnership Unit, European Molecular Biology Laboratory-Universitätsklinikum Heidelberg, Heidelberg, Germany. john.briggs@embl.de.
authors.forename: John A G
authors.initials: JA
authors.lastname: Briggs
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D002213:Capsid / Q000737:chemistry*; D020285:Cryoelectron Microscopy; D024882:Drug Resistance, Viral / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D008956:Models, Chemical; D009154:Mutation; D010455:Peptides / Q000737:chemistry; D011487:Protein Conformation; D059748:Proteolysis; D019065:Virus Assembly; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000737:chemistry* / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D010455:Peptides; D054301:gag Gene Products, Human Immunodeficiency Virus