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CryoET structures of immature HIV Gag reveal six-helix bundle

DOI: 10.1038/s42003-021-01999-1 DOI Help

Authors: Luiza Mendonca (Wellcome Trust Centre for Human Genetics, University of Oxford) , Dapeng Sun (Wellcome Trust Centre for Human Genetics, University of Oxford; University of Pittsburgh School of Medicine) , Jiying Ning (University of Pittsburgh School of Medicine) , Jiwei Liu (Wellcome Trust Centre for Human Genetics, University of Oxford) , Abhay Kotecha (Thermo Fisher Scientific) , Mateusz Olek (Diamond Light Source; University of York) , Thomas Frosio (Diamond Light Source) , Xiaofeng Fu (University of Pittsburgh School of Medicine) , Benjamin A. Himes (University of Pittsburgh School of Medicine) , Alex B. Kleinpeter (National Cancer Institute) , Eric O. Freed (National Cancer Institute) , Jing Zhou (Vanderbilt University Medical Center) , Christopher Aiken (Vanderbilt University Medical Center) , Peijun Zhang (Wellcome Trust Centre for Human Genetics, University of Oxford; University of Pittsburgh School of Medicine; Diamond Light Source)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Communications Biology , VOL 4

State: Published (Approved)
Published: April 2021
Diamond Proposal Number(s): 18477 , 21005 , 21004

Open Access Open Access

Abstract: Gag is the HIV structural precursor protein which is cleaved by viral protease to produce mature infectious viruses. Gag is a polyprotein composed of MA (matrix), CA (capsid), SP1, NC (nucleocapsid), SP2 and p6 domains. SP1, together with the last eight residues of CA, have been hypothesized to form a six-helix bundle responsible for the higher-order multimerization of Gag necessary for HIV particle assembly. However, the structure of the complete six-helix bundle has been elusive. Here, we determined the structures of both Gag in vitro assemblies and Gag viral-like particles (VLPs) to 4.2 Å and 4.5 Å resolutions using cryo-electron tomography and subtomogram averaging by emClarity. A single amino acid mutation (T8I) in SP1 stabilizes the six-helix bundle, allowing to discern the entire CA-SP1 helix connecting to the NC domain. These structures provide a blueprint for future development of small molecule inhibitors that can lock SP1 in a stable helical conformation, interfere with virus maturation, and thus block HIV-1 infection.

Diamond Keywords: Human Immunodeficiency Virus (HIV); Viruses

Subject Areas: Biology and Bio-materials, Medicine

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios I-Titan Krios I at Diamond , Krios II-Titan Krios II at Diamond , Krios III-Titan Krios III at Diamond

Added On: 19/04/2021 10:33

Documents:
s42003-021-01999-1.pdf

Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Drug Discovery Infectious Diseases Pathogens Structural biology

Technical Tags:

Imaging Microscopy Tomography Electron Microscopy (EM) Cryo Electron Tomography (Cryo ET) Cryo Electron Microscopy (Cryo EM)