Structural basis for the inhibitory efficacy of efavirenz (DMP-266), MSC194 and PNU142721 towards the HIV-1 RT K103N mutant
Structural basis for the inhibitory efficacy of efavirenz (DMP-266), MSC194 and PNU142721 towards the HIV-1 RT K103N mutant
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DOI：
10.1046/j.1432-1327.2002.02811.x
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发表时间：
2002-03-01
期刊：
影响因子：
--
通讯作者：
Unge, T
中科院分区：
文献类型：
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作者：
Lindberg, J;Sigurdsson, S;Unge, T
K103N替代是在对联合治疗无反应的患者中经常观察到的HIV-1 RT突变。药物Efavirenz、MSC194和PNU142721属于新一代nnrti，其特征是对HIV-1 RT中最常见的单点突变（包括K103N突变）具有更好的耐药性。在本研究中，我们对Efavirenz与野生型蛋白和K103N突变体的复合物以及PNU142721和MSC194与K103N突变体的复合物进行了结构观察。结构一致表明，K103N取代仅引起三种抑制剂和结合袋内残基的微小位置调整。因此，与相应的野生型结构相比，这些抑制剂以保守模式结合突变体，而不是通过主要的重排。结构表明，抑制效果的降低应归因于取代的NI 03残基附近化学环境的变化。野生型和K103N突变体复合物之间对抑制剂的疏水和静电相互作用的变化支持了这一点。这些有效的抑制剂通过与N103侧链形成新的相互作用来适应K103N突变。我们的研究结果与Hsiou et al. [Hsiou， Y., Ding， J., Das， K., Clark， A.D. Jr ., Boyer, p.l., Lewi， P., Janssen, p.a.， Kleim]的建议一致。J.P，罗斯纳，M，休斯，S.H.和阿诺德。E. (2001) J. Mol. Biol. 309,437 -445]认为，对K103N突变体具有良好活性的抑制剂可能与突变体天冬酰胺侧链有良好的相互作用，从而补偿由于涉及N103和Y188侧链的氢键网络而稳定突变酶所引起的抗性。
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 NI 03 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.