1BWA

HIV-1 PROTEASE (V82F/I84V) DOUBLE MUTANT COMPLEXED WITH XV638 OF DUPONT PHARMACEUTICALS

1BWA の概要

• エントリーDOI: 10.2210/pdb1bwa/pdb
• 分子名称: PROTEIN (HIV-1 PROTEASE), [4R-(4ALPHA,5ALPHA,6BETA,7BETA)]-3,3'-[[TETRAHYDRO-5,6-DIHYDROXY-2-OXO-4,7-BIS(PHENYLMETHYL)-1H-1,3-DIAZEPINE-1,3(2H)-D IYL] BIS(METHYLENE)]BIS[N-2-THIAZOLYLBENZAMIDE] (3 entities in total)
• 機能のキーワード: hiv-1 protease, hydrolase
• 由来する生物種: Human immunodeficiency virus 1
• 細胞内の位置: Gag-Pol polyprotein: Host cell membrane; Lipid-anchor . Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P04585
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 22406.40

構造登録者

Ala, P.,Chang, C.H. (登録日: 1998-09-22, 公開日: 1998-10-30, 最終更新日: 2024-02-07)

主引用文献

Ala, P.J.,Huston, E.E.,Klabe, R.M.,Jadhav, P.K.,Lam, P.Y.,Chang, C.H.
Counteracting HIV-1 protease drug resistance: structural analysis of mutant proteases complexed with XV638 and SD146, cyclic urea amides with broad specificities.
Biochemistry, 37:15042-15049, 1998

PubMed Abstract: The long-term therapeutic benefit of HIV antiretroviral therapy is still threatened by drug-resistant variants. Mutations in the S1 subsite of the protease are the primary cause for the loss of sensitivity toward many HIV protease inhibitors, including our first-generation cyclic urea-based inhibitors DMP323 and DMP450. We now report the structures of the three active-site mutant proteases V82F, I84V, and V82F/I84V in complex with XV638 and SD146, two P2 analogues of DMP323 that are 8-fold more potent against the wild type and are able to inhibit a broad panel of drug-resistant variants [Jadhav, P. K., et al. (1997) J. Med. Chem. 40, 181-191]. The increased efficacy of XV638 and SD146 is due primarily to an increase in P2-S2 interactions: 30-40% more van der Waals contacts and two to four additional hydrogen bonds. Furthermore, because these new interactions do not perturb other subsites in the protease, it appears that the large complementary surface areas of their P2 substituents compensate for the loss of P1-S1 interactions and reduce the probability of selecting for drug-resistant variants.

PubMed: 9790666
DOI: 10.1021/bi980386e

実験手法

X-RAY DIFFRACTION (1.9 Å)