1k6t
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LACK OF SYNERGY FOR INHIBITORS TARGETING A MULTI-DRUG RESISTANT HIV-1 PROTEASE
OverviewOverview
The three-dimensional structures of indinavir and three newly synthesized, indinavir analogs in complex with a multi-drug-resistant variant (L63P, V82T, I84V) of HIV-1 protease were determined to approximately 2.2 A, resolution. Two of the three analogs have only a single modification of, indinavir, and their binding affinities to the variant HIV-1 protease are, enhanced over that of indinavir. However, when both modifications were, combined into a single compound, the binding affinity to the protease, variant was reduced. On close examination, the structural rearrangements, in the protease that occur in the tightest binding inhibitor complex are, mutually exclusive with the structural rearrangements seen in the second, tightest inhibitor complex. This occurs as adaptations in the S1 pocket of, one monomer propagate through the dimer and affect the conformation of the, S1 loop near P81 of the other monomer. Therefore, structural, rearrangements that occur within the protease when it binds to an, inhibitor with a single modification must be accounted for in the design, of inhibitors with multiple modifications. This consideration is necessary, to develop inhibitors that bind sufficiently tightly to drug-resistant, variants of HIV-1 protease to potentially become the next generation of, therapeutic agents.
About this StructureAbout this Structure
1K6T is a Single protein structure of sequence from Human immunodeficiency virus 1 with ACT and XN1 as ligands. Active as HIV-1 retropepsin, with EC number 3.4.23.16 Full crystallographic information is available from OCA.
ReferenceReference
Lack of synergy for inhibitors targeting a multi-drug-resistant HIV-1 protease., King NM, Melnick L, Prabu-Jeyabalan M, Nalivaika EA, Yang SS, Gao Y, Nie X, Zepp C, Heefner DL, Schiffer CA, Protein Sci. 2002 Feb;11(2):418-29. PMID:11790852
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