3NTE

Crystal Structure of the Wild-type Full-Length HIV-1 Capsid Protein

Summary for 3NTE

• Entry DOI: 10.2210/pdb3nte/pdb
• Descriptor: HIV-1 capsid protein, IODIDE ION, Tri-iodode Anion, ... (6 entities in total)
• Functional Keywords: wild type viral protein, viral protein
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 53486.67

Authors

Betts, L.,Yeh, J.I. (deposition date: 2010-07-03, release date: 2010-12-01, Last modification date: 2024-11-20)

Primary citation

Du, S.,Betts, L.,Yang, R.,Shi, H.,Concel, J.,Ahn, J.,Aiken, C.,Zhang, P.,Yeh, J.I.
Structure of the HIV-1 full-length capsid protein in a conformationally trapped unassembled state induced by small-molecule binding.
J.Mol.Biol., 406:371-386, 2011

PubMed Abstract: The capsid (CA) protein plays crucial roles in HIV infection and replication, essential to viral maturation. The absence of high-resolution structural data on unassembled CA hinders the development of antivirals effective in inhibiting assembly. Unlike enzymes that have targetable, functional substrate-binding sites, the CA does not have a known site that affects catalytic or other innate activity, which can be more readily targeted in drug development efforts. We report the crystal structure of the HIV-1 CA, revealing the domain organization in the context of the wild-type full-length (FL) unassembled CA. The FL CA adopts an antiparallel dimer configuration, exhibiting a domain organization sterically incompatible with capsid assembly. A small compound, generated in situ during crystallization, is bound tightly at a hinge site ("H site"), indicating that binding at this interdomain region stabilizes the ADP conformation. Electron microscopy studies on nascent crystals reveal both dimeric and hexameric lattices coexisting within a single condition, in agreement with the interconvertibility of oligomeric forms and supporting the feasibility of promoting assembly-incompetent dimeric states. Solution characterization in the presence of the H-site ligand shows predominantly unassembled dimeric CA, even under conditions that promote assembly. Our structure elucidation of the HIV-1 FL CA and characterization of a potential allosteric binding site provides three-dimensional views of an assembly-defective conformation, a state targeted in, and thus directly relevant to, inhibitor development. Based on our findings, we propose an unprecedented means of preventing CA assembly, by "conformationally trapping" CA in assembly-incompetent conformational states induced by H-site binding.

PubMed: 21146540
DOI: 10.1016/j.jmb.2010.11.027

Experimental method

X-RAY DIFFRACTION (1.95 Å)