Crystal Structures of HIV-1 Reverse Transcriptase in Complex with Carboxanilide Derivatives
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- 作者：Jingshan Ren ; Robert M. Esnouf ; Andrew L. Hopkins ; Jonathan Warren ; Jan Balzarini ; David I. Stuart ; and David K. Stammers
- 刊名：Biochemistry
- 出版年：1998
- 出版时间：October 13, 1998
- 年：1998
- 卷：37
- 期：41
- 页码：14394 - 14403
- 全文大小：286K
- 年卷期：v.37,no.41(October 13, 1998)
- ISSN：1520-4995
文摘
The carboxanilides are nonnucleoside inhibitors (NNIs) of HIV-1 reverse transcriptase (RT),of potential clinical importance. The compounds differ in potency and in their retention of potency in theface of drug resistance mutations. Whereas UC-84, the prototype compound, only weakly inhibits manyRTs bearing single point resistance mutations, inhibition by UC-781 is little affected. It has been proposedthat UC-38 and UC-781 may form quaternary complexes with RT at a site other than the known bindingpocket of other NNIs. X-ray crystal structures of four HIV-1 RT-carboxanilide complexes (UC-10,UC-38, UC-84, and UC-781) reported here reveal that all four inhibitors bind in the usual NNI site,forming binary 1:1 complexes with RT in the absence of substrates with the amide/thioamide bond in cisconformations. For all four complexes the anilide rings of the inhibitors overlap aromatic rings of manyother NNIs bound to RT. In contrast, the second rings of UC-10, UC-84, and UC-781 do not bind inequivalent positions to those of other "two-ring" NNIs such as 
-APA or HEPT derivatives. The bindingmodes most closely resemble that of the structurally dissimilar NNI, Cl-TIBO, with a common hydrogenbond between each carboxanilide NH- group and the main-chain carbonyl oxygen of Lys101. The bindingmodes differ slightly between the UC-10/UC-781 and UC-38/UC-84 pairs of compounds, apparently relatedto the shorter isopropylmethanoyl substituents of the anilide rings of UC-38/UC-84, which draws theserings closer to residues Tyr181 and Tyr188. This in turn explains the differences in the effect of mutatedresidues on the binding of these compounds.
-APA or HEPT derivatives. The bindingmodes most closely resemble that of the structurally dissimilar NNI, Cl-TIBO, with a common hydrogenbond between each carboxanilide NH- group and the main-chain carbonyl oxygen of Lys101. The bindingmodes differ slightly between the UC-10/UC-781 and UC-38/UC-84 pairs of compounds, apparently relatedto the shorter isopropylmethanoyl substituents of the anilide rings of UC-38/UC-84, which draws theserings closer to residues Tyr181 and Tyr188. This in turn explains the differences in the effect of mutatedresidues on the binding of these compounds.