Crystal structures of HIV-1 reverse transcriptase in complex with carboxanilide derivatives
Crystal structures of HIV-1 reverse transcriptase in complex with carboxanilide derivatives
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DOI：
10.1021/bi981309m
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发表时间：
1998-10-13
期刊：
影响因子：
2.9
通讯作者：
Stammers, DK
中科院分区：
文献类型：
--
作者：
Ren, JS;Esnouf, RM;Stammers, DK
酰胺类化合物是HIV-1逆转录酶（RT）的非核苷类抑制剂（NNI），具有潜在的临床意义。这些化合物在效力和在面对耐药性突变时的效力保留方面不同。而原型化合物UC-84仅微弱抑制许多携带单点耐药突变的RT，UC-781的抑制作用几乎不受影响。已经提出UC-38和UC-781可以在除了其他NNI的已知结合口袋之外的位点与RT形成四元复合物。本文报道的四种HIV-1 RT-甲酰苯胺复合物（UC-10、UC-38、UC-84和UC-781）的X射线晶体结构显示，所有四种抑制剂都结合在通常的NNI位点，在不存在具有顺式构象的酰胺/硫代酰胺键的底物的情况下与RT形成二元1：1复合物。对于所有四个复合物的抑制剂的苯胺环重叠的芳香族环的许多其他NNI绑定到RT。相比之下，UC-10，UC-84，和UC-781的第二个环不绑定在等同位置的其他“二环”NNI，如α-APA或HEPT衍生物。结合模式最接近的结构不同的NNI，Cl-TIBO，与每个羧酰苯胺NH-基团和Lys 101的主链羰基氧之间的共同氢键。UC-10/UC-781和UC-38/UC-84对化合物之间的结合模式略有不同，显然与UC-38/UC-84的苯胺环的较短异丙基甲酰基取代基有关，这使这些环更接近残基Tyr 181和Tyr 188。这反过来解释了突变残基对这些化合物结合的影响的差异。
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 the face of drug resistance mutations. Whereas UC-84, the prototype compound, only weakly inhibits many RTs bearing single point resistance mutations, inhibition by UC-781 is little affected. It has been proposed that UC-38 and UC-781 may form quaternary complexes with RT at a site other than the known binding pocket 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 cis conformations. For all four complexes the anilide rings of the inhibitors overlap aromatic rings of many other NNIs bound to RT. In contrast, the second rings of UC-10, UC-84, and UC-781 do not bind in equivalent positions to those of other "two-ring" NNIs such as alpha-APA or HEPT derivatives. The binding modes most closely resemble that of the structurally dissimilar NNI, Cl-TIBO, with a common hydrogen bond between each carboxanilide NH- group and the main-chain carbonyl oxygen of Lys101. The binding modes differ slightly between the UC-10/UC-781 and UC-38/UC-84 pairs of compounds, apparently related to the shorter isopropylmethanoyl substituents of the anilide rings of UC-38/UC-84, which draws these rings closer to residues Tyr181 and Tyr188. This in turn explains the differences in the effect of mutated residues on the binding of these compounds.