1IKX

K103N Mutant HIV-1 Reverse Transcriptase in Complex with the Inhibitor PNU142721

1IKX の概要

• エントリーDOI: 10.2210/pdb1ikx/pdb
• 分子名称: POL POLYPROTEIN, 6-CHLORO-2-(1-FURO[2,3-C]PYRIDIN-5-YL-ETHYLSULFANYL)-PYRIMIDIN-4-YLAMINE, ... (4 entities in total)
• 機能のキーワード: heterodimer, protein-inhibitor complex, transferase
• 由来する生物種: Human immunodeficiency virus 1; 詳細
• 細胞内の位置: Gag-Pol polyprotein: Host cell membrane; Lipid-anchor. Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P03366 P03366
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 114720.08

構造登録者

Lindberg, J.,Unge, T. (登録日: 2001-05-07, 公開日: 2001-06-06, 最終更新日: 2024-02-07)

主引用文献

Lindberg, J.,Sigurdsson, S.,Lowgren, S.,Andersson, H.O.,Sahlberg, C.,Noreen, R.,Fridborg, K.,Zhang, H.,Unge, T.
Structural basis for the inhibitory efficacy of efavirenz (DMP-266), MSC194 and PNU142721 towards the HIV-1 RT K103N mutant.
Eur.J.Biochem., 269:1670-1677, 2002

PubMed Abstract: The K103N substitution is a frequently observed HIV-1 RT mutation in patients who do not respond to combination-therapy. The drugs Efavirenz, MSC194 and PNU142721 belong to the recent generation of NNRTIs characterized by an improved resistance profile to the most common single point mutations within HIV-1 RT, including the K103N mutation. In the present study we present structural observations from Efavirenz in complex with wild-type protein and the K103N mutant and PNU142721 and MSC194 in complex with the K103N mutant. The structures unanimously indicate that the K103N substitution induces only minor positional adjustments of the three inhibitors and the residues lining the binding pocket. Thus, compared to the corresponding wild-type structures, these inhibitors bind to the mutant in a conservative mode rather than through major rearrangements. The structures implicate that the reduced inhibitory efficacy should be attributed to the changes in the chemical environment in the vicinity of the substituted N103 residue. This is supported by changes in hydrophobic and electrostatic interactions to the inhibitors between wild-type and K103N mutant complexes. These potent inhibitors accommodate to the K103N mutation by forming new interactions to the N103 side chain. Our results are consistent with the proposal by Hsiou et al. [Hsiou, Y., Ding, J., Das, K., Clark, A.D. Jr, Boyer, P.L., Lewi, P., Janssen, P.A., Kleim, J.P., Rosner, M., Hughes, S.H. & Arnold, E. (2001) J. Mol. Biol. 309, 437-445] that inhibitors with good activity against the K103N mutant would be expected to have favorable interactions with the mutant asparagines side chain, thereby compensating for resistance caused by stabilization of the mutant enzyme due to a hydrogen-bond network involving the N103 and Y188 side chains.

PubMed: 11895437
DOI: 10.1046/j.1432-1327.2002.02811.x

実験手法

X-RAY DIFFRACTION (2.8 Å)