Structure of HIV-1 protease with KNI-272, a tight-binding transition-state analog containing allophenylnorstatine.
Baldwin, E.T., Bhat, T.N., Gulnik, S., Liu, B., Topol, I.A., Kiso, Y., Mimoto, T., Mitsuya, H., Erickson, J.W.(1995) Structure 3: 581-590
- PubMed: 8590019 
- DOI: https://doi.org/10.1016/s0969-2126(01)00192-7
- Primary Citation of Related Structures:  
1HPX - PubMed Abstract: 
HIV-1 protease (HIV PR), an aspartic protease, cleaves Phe-Pro bonds in the Gag and Gag-Pol viral polyproteins. Substrate-based peptide mimics constitute a major class of inhibitors of HIV PR presently being developed for AIDS treatment. One such compound, KNI-272, which incorporates allophenylnorstatine (Apns)-thioproline (Thp) in place of Phe-Pro, has potent antiviral activity and is undergoing clinical trials. The structure of the enzyme-inhibitor complex should lead to an understanding of the structural basis for its tight binding properties and provide a framework for interpreting the emerging resistance to this drug. The three-dimensional crystal structure of KNI-272 bound to HIV PR has been determined to 2.0 A resolution and used to analyze structure-activity data and drug resistance for the Arg8-->Gln and ILe84-->Val mutations in HIV PR. The conformationally constrained Apns-Thp linkage is favorably recognized in its low energy trans conformation, which results in a symmetric mode of binding to the active-site aspartic acids and also explains the unusual preference of HIV PR for the S, or syn, hydroxyl group of the Apns residue. The inhibitor recognizes the enzyme via hydrogen bonds to three bridging water molecules, including one that is coordinated directly to the catalytic Asp125 residue. The structure of the HIV PR/KNI-272 complex illustrates the importance of limiting the conformational degrees of freedom and of using protein-bound water molecules for building potent inhibitors. The binding mode of HIV PR inhibitors can be predicted from the stereochemical relationship between adjacent hydroxyl-bearing and side chain bearing carbon atoms of the P1 substituent. Our structure also provides a framework for designing analogs targeted to drug-resistant mutant enzymes.
Organizational Affiliation: 
Frederick Biomedical Supercomputing Center, SAIC-Frederick, NCI-Frederick Cancer Research and Development Center, Maryland 21702, USA.