1ZTZ

Crystal structure of HIV protease- metallacarborane complex

1ZTZ の概要

• エントリーDOI: 10.2210/pdb1ztz/pdb
• 関連するPDBエントリー: 1NH0
• 分子名称: PROTEASE RETROPEPSIN, autoproteolytic tetrapeptide, COBALT BIS(1,2-DICARBOLLIDE), ... (4 entities in total)
• 機能のキーワード: rational drug design; hiv protease inhibitors; aspartic proteases; carboranes; metallacarboranes, 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 : P03367
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 22545.41

構造登録者

Cigler, P.,Kozisek, M.,Rezacova, P.,Brynda, J.,Otwinowski, Z.,Sedlacek, J.,Bodem, J.,Kraeusslich, H.-G.,Kral, V.,Konvalinka, J. (登録日: 2005-05-28, 公開日: 2005-11-01, 最終更新日: 2023-08-23)

主引用文献

Cigler, P.,Kozisek, M.,Rezacova, P.,Brynda, J.,Otwinowski, Z.,Pokorna, J.,Plesek, J.,Gruner, B.,Doleckova-Maresova, L.,Masa, M.,Sedlacek, J.,Bodem, J.,Kraeusslich, H.-G.,Kral, V.,Konvalinka, J.
From nonpeptide toward noncarbon protease inhibitors: Metallacarboranes as specific and potent inhibitors of HIV protease
Proc.Natl.Acad.Sci.USA, 102:15394-15399, 2005

PubMed Abstract: HIV protease (PR) represents a prime target for rational drug design, and protease inhibitors (PI) are powerful antiviral drugs. Most of the current PIs are pseudopeptide compounds with limited bioavailability and stability, and their use is compromised by high costs, side effects, and development of resistant strains. In our search for novel PI structures, we have identified a group of inorganic compounds, icosahedral metallacarboranes, as candidates for a novel class of nonpeptidic PIs. Here, we report the potent, specific, and selective competitive inhibition of HIV PR by substituted metallacarboranes. The most active compound, sodium hydrogen butylimino bis-8,8-[5-(3-oxa-pentoxy)-3-cobalt bis(1,2-dicarbollide)]di-ate, exhibited a K(i) value of 2.2 nM and a submicromolar EC(50) in antiviral tests, showed no toxicity in tissue culture, weakly inhibited human cathepsin D and pepsin, and was inactive against trypsin, papain, and amylase. The structure of the parent cobalt bis(1,2-dicarbollide) in complex with HIV PR was determined at 2.15 A resolution by protein crystallography and represents the first carborane-protein complex structure determined. It shows the following mode of PR inhibition: two molecules of the parent compound bind to the hydrophobic pockets in the flap-proximal region of the S3 and S3' subsites of PR. We suggest, therefore, that these compounds block flap closure in addition to filling the corresponding binding pockets as conventional PIs. This type of binding and inhibition, chemical and biological stability, low toxicity, and the possibility to introduce various modifications make boron clusters attractive pharmacophores for potent and specific enzyme inhibition.

PubMed: 16227435
DOI: 10.1073/pnas.0507577102

実験手法

X-RAY DIFFRACTION (2.15 Å)