1K6C

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

1K6C の概要

• エントリーDOI: 10.2210/pdb1k6c/pdb
• 関連するPDBエントリー: 1K6P 1K6T 1K6V
• 分子名称: POL polyprotein, ACETATE ION, N-[2(R)-HYDROXY-1(S)-INDANYL]-5-[(2(S)-TERTIARY BUTYLAMINOCARBONYL)-4(3-PYRIDYLMETHYL)PIPERAZINO]-4(S)-HYDROXY-2(R)-PHENYLMETHYLPENTANAMIDE, ... (4 entities in total)
• 機能のキーワード: indinavir, inhibitor recognition, drug resistance, hiv-1 protease, hydrolase
• 由来する生物種: Human immunodeficiency virus 1
• 細胞内の位置: 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
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 22572.51

構造登録者

Schiffer, C.A. (登録日: 2001-10-15, 公開日: 2002-02-06, 最終更新日: 2023-08-16)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.2 Å)