3PJ6

Crystal Structures of Multidrug-Resistant Clinical Isolate 769 HIV-1 Protease Variants

3PJ6 の概要

• エントリーDOI: 10.2210/pdb3pj6/pdb
• 関連するPDBエントリー: 1TW7 3OQ7 3OQA 3OQD
• 分子名称: HIV protease (2 entities in total)
• 機能のキーワード: alternate conformations of pro81, proline switch, wide-open flaps, expanded active site cavity, hydrolase
• 由来する生物種: Human Immunodeficiency Virus 1 (HIV-1)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 10725.58

構造登録者

Yedidi, R.S.,Proteasa, G.,Martinez-Cajas, J.L.,Vickrey, J.F.,Martin, P.D.,Wawrzak, Z.,Kovari, L.C. (登録日: 2010-11-08, 公開日: 2011-04-06, 最終更新日: 2023-09-06)

主引用文献

Yedidi, R.S.,Proteasa, G.,Martinez, J.L.,Vickrey, J.F.,Martin, P.D.,Wawrzak, Z.,Liu, Z.,Kovari, I.A.,Kovari, L.C.
Contribution of the 80s loop of HIV-1 protease to the multidrug-resistance mechanism: crystallographic study of MDR769 HIV-1 protease variants.
Acta Crystallogr.,Sect.D, 67:524-532, 2011

PubMed Abstract: The flexible flaps and the 80s loops (Pro79-Ile84) of HIV-1 protease are crucial in inhibitor binding. Previously, it was reported that the crystal structure of multidrug-resistant 769 (MDR769) HIV-1 protease shows a wide-open conformation of the flaps owing to conformational rigidity acquired by the accumulation of mutations. In the current study, the effect of mutations on the conformation of the 80s loop of MDR769 HIV-1 protease variants is reported. Alternate conformations of Pro81 (proline switch) with a root-mean-square deviation of 3-4.8 Å in the C(α) atoms of the I10V mutant and a side chain with a `flipped-out' conformation in the A82F mutant cause distortion in the S1/S1' binding pockets that affects inhibitor binding. The A82S and A82T mutants show local changes in the electrostatics of inhibitor binding owing to the mutation from nonpolar to polar residues. In summary, the crystallographic studies of four variants of MDR769 HIV-1 protease presented in this article provide new insights towards understanding the drug-resistance mechanism as well as a basis for design of future protease inhibitors with enhanced potency.

PubMed: 21636892
DOI: 10.1107/S0907444911011541

実験手法

X-RAY DIFFRACTION (2.25 Å)