1K6P: Lack Of Synergy For Inhibitors Targeting A Multi-Drug Resistant Hiv-1 Protease

Citation:
Abstract
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.
PDB ID: 1K6PDownload
MMDB ID: 18418
PDB Deposition Date: 2001/10/16
Updated in MMDB: 2012/11
Experimental Method:
x-ray diffraction
Resolution: 2.2  Å
Source Organism:
Similar Structures:
Biological Unit for 1K6P: dimeric; determined by author and by software (PISA)
Molecular Components in 1K6P
Label Count Molecule
Proteins (2 molecules)
2
POL Polyprotein
Molecule annotation
Chemicals (10 molecules)
1
9
2
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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