National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
P50 GM082545-06
米国
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
P01 AI100148
米国
引用
ジャーナル: Cell Host Microbe / 年: 2018 タイトル: Partially Open HIV-1 Envelope Structures Exhibit Conformational Changes Relevant for Coreceptor Binding and Fusion. 著者: Haoqing Wang / Christopher O Barnes / Zhi Yang / Michel C Nussenzweig / Pamela J Bjorkman / 要旨: HIV-1 Env, a trimer of gp120-gp41 heterodimers, mediates membrane fusion after binding host receptor CD4. Receptor binding displaces V1V2 loops from Env's apex, allowing coreceptor binding and ...HIV-1 Env, a trimer of gp120-gp41 heterodimers, mediates membrane fusion after binding host receptor CD4. Receptor binding displaces V1V2 loops from Env's apex, allowing coreceptor binding and opening Env to enable gp41-mediated fusion. We present 3.54 Å and 4.06 Å cryoelectron microscopy structures of partially open soluble native-like Env trimers (SOSIPs) bound to CD4. One structure, a complex with a coreceptor-mimicking antibody that binds both CD4 and gp120, stabilizes the displaced V1V2 and reveals its structure. Comparing partially and fully open Envs with closed Envs shows that gp41 rearrangements are independent of the CD4-induced rearrangements that result in V1V2 displacement and formation of a 4-stranded bridging sheet. These findings suggest ordered conformational changes before coreceptor binding: (1) gp120 opening inducing side-chain rearrangements and a compact gp41 central helix conformation, and (2) 4-stranded bridging-sheet formation and V1V2 displacement. These analyses illuminate potential receptor-induced Env changes and inform design of therapeutics disrupting viral entry.
Sharpened map of focused refinement of 21c, gp120, and sCD4. Used for model building and refinement of V1V2 region, 21c-gp120 interface, and 21c-sCD4 interface.
詳細: A model structure of the Env-sCD4-21c-8ANC195 complex was generated by replacing 17b Fab with 21c Fab in the partially-open BG505-sCD4-17b-8ANC195 structure (PDB 5THR). The 21c Fab binding ...詳細: A model structure of the Env-sCD4-21c-8ANC195 complex was generated by replacing 17b Fab with 21c Fab in the partially-open BG505-sCD4-17b-8ANC195 structure (PDB 5THR). The 21c Fab binding angle was determined by aligning gp120s from the gp120-sCD4-21c crystal structure (PDB 3LQA) and the BG505-sCD4-17b-8ANC195 structure. The modeled structure was low-pass filtered to 60 Angstroms to serve as the initial 3D reference.