3FX5

Structure of HIV-1 Protease in Complex with Potent Inhibitor KNI-272 Determined by High Resolution X-ray Crystallography

Summary for 3FX5

• Entry DOI: 10.2210/pdb3fx5/pdb
• Related: 1HPX 2ZYE
• Related PRD ID: PRD_000562
• Descriptor: protease, GLYCEROL, (4R)-N-tert-butyl-3-[(2S,3S)-2-hydroxy-3-({N-[(isoquinolin-5-yloxy)acetyl]-S-methyl-L-cysteinyl}amino)-4-phenylbutanoyl]-1,3-thiazolidine-4-carboxamide, ... (4 entities in total)
• Functional Keywords: acid protease, homodimer, protease, hydrolase, nucleotidyltransferase, transferase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus 1 (HIV-1)
• Total number of polymer chains: 2
• Total formula weight: 22425.47

Authors

Adachi, M.,Ohhara, T.,Tamada, T.,Okazaki, N.,Kuroki, R. (deposition date: 2009-01-20, release date: 2009-03-24, Last modification date: 2023-11-01)

Primary citation

Adachi, M.,Ohhara, T.,Kurihara, K.,Tamada, T.,Honjo, E.,Okazaki, N.,Arai, S.,Shoyama, Y.,Kimura, K.,Matsumura, H.,Sugiyama, S.,Adachi, H.,Takano, K.,Mori, Y.,Hidaka, K.,Kimura, T.,Hayashi, Y.,Kiso, Y.,Kuroki, R.
Structure of HIV-1 protease in complex with potent inhibitor KNI-272 determined by high-resolution X-ray and neutron crystallography.
Proc.Natl.Acad.Sci.USA, 2009

PubMed Abstract: HIV-1 protease is a dimeric aspartic protease that plays an essential role in viral replication. To further understand the catalytic mechanism and inhibitor recognition of HIV-1 protease, we need to determine the locations of key hydrogen atoms in the catalytic aspartates Asp-25 and Asp-125. The structure of HIV-1 protease in complex with transition-state analog KNI-272 was determined by combined neutron crystallography at 1.9-A resolution and X-ray crystallography at 1.4-A resolution. The resulting structural data show that the catalytic residue Asp-25 is protonated and that Asp-125 (the catalytic residue from the corresponding diad-related molecule) is deprotonated. The proton on Asp-25 makes a hydrogen bond with the carbonyl group of the allophenylnorstatine (Apns) group in KNI-272. The deprotonated Asp-125 bonds to the hydroxyl proton of Apns. The results provide direct experimental evidence for proposed aspects of the catalytic mechanism of HIV-1 protease and can therefore contribute substantially to the development of specific inhibitors for therapeutic application.

PubMed: 19273847
DOI: 10.1073/pnas.0809400106

Experimental method

X-RAY DIFFRACTION (0.93 Å)