4FAF

Substrate CA/p2 in Complex with a Human Immunodeficiency Virus Type 1 Protease Variant

Summary for 4FAF

• Entry DOI: 10.2210/pdb4faf/pdb
• Related: 1TW7 3OQ7 4FAE
• Descriptor: HIV-1 protease, substrate CA/p2 peptide (3 entities in total)
• Functional Keywords: protease, viral protein
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 3
• Total formula weight: 22405.33

Authors

Wang, Y.,Dewdney, T.G.,Liu, Z.,Reiter, S.J.,Brunzelle, J.S.,Kovari, I.A.,Kovari, L.C. (deposition date: 2012-05-22, release date: 2012-08-29, Last modification date: 2024-05-22)

Primary citation

Wang, Y.,Dewdney, T.G.,Liu, Z.,Reiter, S.J.,Brunzelle, J.S.,Kovari, I.A.,Kovari, L.C.
Higher Desolvation Energy Reduces Molecular Recognition in Multi-Drug Resistant HIV-1 Protease.
Biology (Basel), 1:81-93, 2012

PubMed Abstract: Designing HIV-1 protease inhibitors that overcome drug-resistance is still a challenging task. In this study, four clinical isolates of multi-drug resistant HIV-1 proteases that exhibit resistance to all the US FDA-approved HIV-1 protease inhibitors and also reduce the substrate recognition ability were examined. A multi-drug resistant HIV-1 protease isolate, MDR 769, was co-crystallized with the p2/NC substrate and the mutated CA/p2 substrate, CA/p2 P1'F. Both substrates display different levels of molecular recognition by the wild-type and multi-drug resistant HIV-1 protease. From the crystal structures, only limited differences can be identified between the wild-type and multi-drug resistant protease. Therefore, a wild-type HIV-1 protease and four multi-drug resistant HIV-1 proteases in complex with the two peptides were modeled based on the crystal structures and examined during a 10 ns-molecular dynamics simulation. The simulation results reveal that the multi-drug resistant HIV-1 proteases require higher desolvation energy to form complexes with the peptides. This result suggests that the desolvation of the HIV-1 protease active site is an important step of protease-ligand complex formation as well as drug resistance. Therefore, desolvation energy could be considered as a parameter in the evaluation of future HIV-1 protease inhibitor candidates.

PubMed: 24832048
DOI: 10.3390/biology1010081

Experimental method

X-RAY DIFFRACTION (2.1 Å)