5U7M

Crystal Structure of HIV-1 BG505 SOSIP.664 Prefusion Env Trimer Bound to Small Molecule HIV-1 Entry Inhibitor BMS-378806 in Complex with Human Antibodies PGT122 and 35O22 at 3.8 Angstrom

5U7M の概要

• エントリーDOI: 10.2210/pdb5u7m/pdb
• 関連するPDBエントリー: 5U7O
• 分子名称: 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, ... (15 entities in total)
• 機能のキーワード: hiv-1 entry, small molecule, inhibitor, viral protein-immune system complex, viral protein/immune system
• 由来する生物種: Human immunodeficiency virus 1; 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 180977.01

構造登録者

Pancera, M.,Lai, Y.-T.,Kwong, P.D. (登録日: 2016-12-12, 公開日: 2017-08-30, 最終更新日: 2024-10-09)

主引用文献

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

実験手法

X-RAY DIFFRACTION (3.025 Å)