1K6T

LACK OF SYNERGY FOR INHIBITORS TARGETING A MULTI-DRUG RESISTANT HIV-1 PROTEASE

Summary for 1K6T

• Entry DOI: 10.2210/pdb1k6t/pdb
• Related: 1K6C 1K6P 1K6V
• Descriptor: POL polyprotein, ACETATE ION, N-[2-HYDROXY-1-INDANYL]-5-[(2-TERTIARYBUTYLAMINOCARBONYL)-4(3-PYRIDYLMETHYL)PIPERAZINO]-4-HYDROXY-2-(1-PHENYLETHYL)-PEN TANAMIDE, ... (4 entities in total)
• Functional Keywords: indinavir, inhibitor recognition, hiv-1 protease, drug resistance, hydrolase
• Biological source: Human immunodeficiency virus 1
• Cellular location: Matrix protein p17: Virion (Potential). Capsid protein p24: Virion (Potential). Nucleocapsid protein p7: Virion (Potential). Reverse transcriptase/ribonuclease H: Virion (Potential). Integrase: Virion (Potential): P35963
• Total number of polymer chains: 2
• Total formula weight: 22527.49

Authors

Schiffer, C.A. (deposition date: 2001-10-17, release date: 2002-02-06, Last modification date: 2023-08-16)

Primary citation

King, N.M.,Melnick, L.,Prabu-Jeyabalan, M.,Nalivaika, E.A.,Yang, S.S.,Gao, Y.,Nie, X.,Zepp, C.,Heefner, D.L.,Schiffer, C.A.
Lack of synergy for inhibitors targeting a multi-drug-resistant HIV-1 protease.
Protein Sci., 11:418-429, 2002

PubMed 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.

PubMed: 11790852
DOI: 10.1110/ps.2520102

Experimental method

X-RAY DIFFRACTION (2.25 Å)