5U7O

Crystal Structure of HIV-1 BG505 SOSIP.664 Prefusion Env Trimer Bound to Small Molecule HIV-1 Entry Inhibitor BMS-626529 in Complex with Human Antibodies PGT122 and 35O22 at 3.8 Angstrom

Summary for 5U7O

• Entry DOI: 10.2210/pdb5u7o/pdb
• Related: 5U7M
• Descriptor: Envelope glycoprotein gp160, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (16 entities in total)
• Functional Keywords: hiv-1 entry, small molecule, inhibitor, viral protein-immune system complex, viral protein/immune system
• Biological source: Human immunodeficiency virus 1; More
• Total number of polymer chains: 6
• Total formula weight: 181409.40

Authors

Pancera, M.,Lai, Y.-T.,Kwong, P.D. (deposition date: 2016-12-12, release date: 2017-08-30, Last modification date: 2024-10-23)

Primary citation

Pancera, M.,Lai, Y.T.,Bylund, T.,Druz, A.,Narpala, S.,O'Dell, S.,Schon, A.,Bailer, R.T.,Chuang, G.Y.,Geng, H.,Louder, M.K.,Rawi, R.,Soumana, D.I.,Finzi, A.,Herschhorn, A.,Madani, N.,Sodroski, J.,Freire, E.,Langley, D.R.,Mascola, J.R.,McDermott, A.B.,Kwong, P.D.
Crystal structures of trimeric HIV envelope with entry inhibitors BMS-378806 and BMS-626529.
Nat. Chem. Biol., 13:1115-1122, 2017

PubMed Abstract: The HIV-1 envelope (Env) spike is a conformational machine that transitions between prefusion (closed, CD4- and CCR5-bound) and postfusion states to facilitate HIV-1 entry into cells. Although the prefusion closed conformation is a potential target for inhibition, development of small-molecule leads has been stymied by difficulties in obtaining structural information. Here, we report crystal structures at 3.8-Å resolution of an HIV-1-Env trimer with BMS-378806 and a derivative BMS-626529 for which a prodrug version is currently in Phase III clinical trials. Both lead candidates recognized an induced binding pocket that was mostly excluded from solvent and comprised of Env elements from a conserved helix and the β20-21 hairpin. In both structures, the β20-21 region assumed a conformation distinct from prefusion-closed and CD4-bound states. Together with biophysical and antigenicity characterizations, the structures illuminate the allosteric and competitive mechanisms by which these small-molecule leads inhibit CD4-induced structural changes in Env.

PubMed: 28825711
DOI: 10.1038/nchembio.2460

Experimental method

X-RAY DIFFRACTION (3.031 Å)