1FB7

CRYSTAL STRUCTURE OF AN IN VIVO HIV-1 PROTEASE MUTANT IN COMPLEX WITH SAQUINAVIR: INSIGHTS INTO THE MECHANISMS OF DRUG RESISTANCE

1FB7 の概要

• エントリーDOI: 10.2210/pdb1fb7/pdb
• 関連するBIRD辞書のPRD_ID: PRD_000454
• 分子名称: HIV-1 PROTEASE, (2S)-N-[(2S,3R)-4-[(2S,3S,4aS,8aS)-3-(tert-butylcarbamoyl)-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-3-hydroxy-1 -phenyl-butan-2-yl]-2-(quinolin-2-ylcarbonylamino)butanediamide (3 entities in total)
• 機能のキーワード: hiv protease, mutant, drug resistance, viral protein, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Human immunodeficiency virus 1
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 11520.69

構造登録者

Hong, L.,Zhang, X.C.,Hartsuck, J.A.,Tang, J. (登録日: 2000-07-14, 公開日: 2000-12-13, 最終更新日: 2024-02-07)

主引用文献

Hong, L.,Zhang, X.C.,Hartsuck, J.A.,Tang, J.
Crystal structure of an in vivo HIV-1 protease mutant in complex with saquinavir: insights into the mechanisms of drug resistance.
Protein Sci., 9:1898-1904, 2000

PubMed Abstract: Saquinavir is a widely used HIV-1 protease inhibitor drug for AIDS therapy. Its effectiveness, however, has been hindered by the emergence of resistant mutations, a common problem for inhibitor drugs that target HIV-1 viral enzymes. Three HIV-1 protease mutant species, G48V, L90M, and G48V/L90M double mutant, are associated in vivo with saquinavir resistance by the enzyme (Jacobsen et al., 1996). Kinetic studies on these mutants demonstrate a 13.5-, 3-, and 419-fold increase in Ki values, respectively, compared to the wild-type enzyme (Ermolieff J, Lin X, Tang J, 1997, Biochemistry 36:12364-12370). To gain an understanding of how these mutations modulate inhibitor binding, we have solved the HIV-1 protease crystal structure of the G48V/L90M double mutant in complex with saquinavir at 2.6 A resolution. This mutant complex is compared with that of the wild-type enzyme bound to the same inhibitor (Krohn A, Redshaw S, Richie JC, Graves BJ, Hatada MH, 1991, J Med Chem 34:3340-3342). Our analysis shows that to accommodate a valine side chain at position 48, the inhibitor moves away from the protease, resulting in the formation of larger gaps between the inhibitor P3 subsite and the flap region of the enzyme. Other subsites also demonstrate reduced inhibitor interaction due to an overall change of inhibitor conformation. The new methionine side chain at position 90 has van der Waals interactions with main-chain atoms of the active site residues resulting in a decrease in the volume and the structural flexibility of S1/S1' substrate binding pockets. Indirect interactions between the mutant methionine side chain and the substrate scissile bond or the isostere part of the inhibitor may differ from those of the wild-type enzyme and therefore may facilitate catalysis by the resistant mutant.

PubMed: 11106162

実験手法

X-RAY DIFFRACTION (2.6 Å)