4HDF

Crystal Structure of HIV-1 protease mutants V82A complexed with inhibitor GRL-0519

4HDF の概要

• エントリーDOI: 10.2210/pdb4hdf/pdb
• 関連するPDBエントリー: 3OK9 4HDB 4HDP 4HE9 4HEG
• 分子名称: HIV-1 Protease, CHLORIDE ION, (3R,3aS,3bR,6aS,7aS)-octahydrodifuro[2,3-b:3',2'-d]furan-3-yl [(1S,2R)-1-benzyl-2-hydroxy-3-{[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino}propyl]carbamate, ... (4 entities in total)
• 機能のキーワード: aspartic acid protease, drug resistance, hiv-1 protease inhibitor grl-0519, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Human immunodeficiency virus type 1 (HIV-1)
• 細胞内の位置: Matrix protein p17: Virion (Potential). Capsid protein p24: Virion (Potential). Nucleocapsid protein p7: Virion (Potential). Reverse transcriptase/ribonuclease H: Virion (Potential). Integrase: Virion (Potential): P03367
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 22065.41

構造登録者

Zhang, H.,Wang, Y.-F.,Weber, I.T. (登録日: 2012-10-02, 公開日: 2013-08-14, 最終更新日: 2023-09-20)

主引用文献

Zhang, H.,Wang, Y.F.,Shen, C.H.,Agniswamy, J.,Rao, K.V.,Xu, C.X.,Ghosh, A.K.,Harrison, R.W.,Weber, I.T.
Novel P2 tris-tetrahydrofuran group in antiviral compound 1 (GRL-0519) fills the S2 binding pocket of selected mutants of HIV-1 protease.
J.Med.Chem., 56:1074-1083, 2013

PubMed Abstract: GRL-0519 (1) is a potent antiviral inhibitor of HIV-1 protease (PR) possessing tris-tetrahydrofuran (tris-THF) at P2. The high resolution X-ray crystal structures of inhibitor 1 in complexes with single substitution mutants PR(R8Q), PR(D30N), PR(I50V), PR(I54M), and PR(V82A) were analyzed in relation to kinetic data. The smaller valine side chain in PR(I50V) eliminated hydrophobic interactions with inhibitor and the other subunit consistent with 60-fold worse inhibition. Asn30 in PR(D30N) showed altered interactions with neighboring residues and 18-fold worse inhibition. Mutations V82A and I54M showed compensating structural changes consistent with 6-7-fold lower inhibition. Gln8 in PR(R8Q) replaced the ionic interactions of wild type Arg8 with hydrogen bond interactions without changing the inhibition significantly. The carbonyl oxygen of Gly48 showed two alternative conformations in all structures likely due to the snug fit of the large tris-THF group in the S2 subsite in agreement with high antiviral efficacy of 1 on resistant virus.

PubMed: 23298236
DOI: 10.1021/jm301519z

実験手法

X-RAY DIFFRACTION (1.29 Å)