1HTF

X-RAY CRYSTALLOGRAPHIC STUDIES OF A SERIES OF PENICILLIN-DERIVED ASYMMETRIC INHIBITORS OF HIV-1 PROTEASE

1HTF の概要

• エントリーDOI: 10.2210/pdb1htf/pdb
• 分子名称: HIV-1 PROTEASE, 2-(BENZYLCARBAMOYL-PHENYLACETYLAMINO-METHYL)-5,5-DIMETHYL-THIAZOLIDINE-4-CARBOXYLIC ACID (HYDROXYMETHYL-2-PHENYLETHYL)AMIDE (3 entities in total)
• 機能のキーワード: hydrolase(acid proteinase)
• 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 : P03366
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 22756.98

構造登録者

Jhoti, H.,Wonacott, A.,Murray-Rust, P. (登録日: 1994-04-29, 公開日: 1994-07-31, 最終更新日: 2024-06-12)

主引用文献

Jhoti, H.,Singh, O.M.,Weir, M.P.,Cooke, R.,Murray-Rust, P.,Wonacott, A.
X-ray crystallographic studies of a series of penicillin-derived asymmetric inhibitors of HIV-1 protease.
Biochemistry, 33:8417-8427, 1994

PubMed Abstract: In the development of a treatment for AIDS, the HIV-1 protease has been identified as a good target enzyme for inhibitor design. We previously reported a series of dimeric penicillin-derived C2-symmetric HIV-1 protease inhibitors [Humber, D., et al. (1993) J. Med. Chem. 36, 3120-3128]. In an attempt to reduce the size and optimize the binding of these C2-symmetric inhibitors, molecular modeling studies led to a novel series of monomeric penicillin-derived inhibitors of HIV-1 protease. The binding modes of these monomeric inhibitors have been characterized by X-ray crystallographic and NMR studies. Crystal structures of HIV-1 protease complexed to three inhibitors (GR123976, GR126045, and GR137615) from this series identify the molecular details of the interactions. The binding of GR123976 (IC50 = 2.3 microM) exhibits good hydrophobic contacts but few electrostatic interactions. A strategy of structure-based design and chemical synthesis led to the elaboration of GR123976 to optimize interactions with the protein. Crystallographic analysis of HIV-1 protease complexed to GR126045 and GR137615 identified these interactions with the catalytic aspartates and the protein binding pockets. The crystal structures of the three complexes confirm the presence of the major interactions modeled in order to optimize potency and reveal details of the molecular recognition by HIV-1 protease of this novel series of nonpeptidic inhibitors.

PubMed: 8031777
DOI: 10.1021/bi00194a005

実験手法

X-RAY DIFFRACTION (2.2 Å)