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Efavirenz Binding Site in HIV-1 Reverse Transcriptase Monomers

机译：HIV-1逆转录酶单体中的依夫韦伦结合位点

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摘要

Efavirenz (EFV) is a potent nonnucleoside reverse transcriptase inhibitor (NNRTI) used in thentreatment of AIDS.NNRTIs bind in a hydrophobic pocket located in the p66 subunit of reverse transcriptasen(RT), which is not present in crystal structures of RT without an inhibitor. Recent studies showed thatnmonomeric forms of the p66 and p51 subunits bind efavirenz withmicromolar affinity. The effect of efavirenznon the solution conformations of p66 and p51 monomers was studied by hydrogen-deuterium exchange massnspectrometry (HXMS) and Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS).nHXMS data reveal that five peptides, four of which contain efavirenz contact residues seen in the crystalnstructure of the RT-EFV complex, exhibit a reduced level of exchange in monomer-EFV complexes.nMoreover, peptide 232-246 undergoes slowcooperative unfolding-refolding in the boundmonomers, but at anrate much slower than that observed in the p66 subunit of the RT heterodimer [Seckler, J. M., Howard,nK. J., Barkley,M. D., andWintrode, P. L. (2009) Biochemistry 48, 7646-7655]. These results suggest that thenefavirenz binding site on p66 and p51monomers is similar to theNNRTI binding pocket in the p66 subunit ofnRT.Nanoelectrospray ionization FT-ICRmass spectra indicate that the intactmonomers each have (at least)ntwo different conformations. In the presence of efavirenz, the mass spectra change significantly and suggestnthat p51 adopts a single, more compact conformation, whereas p66 undergoes facile, electrospray-inducedncleavage. The population shift is consistent with a selected-fit binding mechanism.
机译：Efavirenz（EFV）是一种有效的非核苷类逆转录酶抑制剂（NNRTI），用于随后的AIDS治疗。NNRTIs结合在位于逆转录酶（RT）p66亚基的疏水口袋中，而没有抑制剂则在RT的晶体结构中不存在。最近的研究表明，p66和p51亚基的单体形式以微摩尔亲和力结合依非韦伦。通过氢-氘交换质谱（HXMS）和傅立叶变换离子回旋共振质谱（FT-ICR MS）研究了依非韦伦对p66和p51单体溶液构象的影响.nHXMS数据显示五个肽，其中四个包含依非韦伦在RT-EFV络合物的晶体结构中看到的接触残基在单体-EFV络合物中显示出降低的交换水平。此外，肽232-246在结合单体中经历缓慢的协同解折叠-折叠，但比在EF-EFV络合物中观察到的慢得多。 RT异二聚体的p66亚基[Seckler，JM，Howard，nK。 J.，Barkley，M. D.，and Wintrode，P. L.（2009）Biochemistry 48，7646-7655]。这些结果表明，p66和p51单体上的efefavirenz结合位点与nRT的p66亚单位中的NNRTI结合口袋相似。纳米电喷雾电离FT-ICRmass光谱表明，完整单体分别具有（至少）两种不同的构象。在依法韦仑的存在下，质谱发生显着变化，表明p51采用单个更紧凑的构象，而p66则经历了容易的，电喷雾诱导的裂解。人口迁移与选择拟合约束机制一致。

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    《Biochemistry》 |2010年第49期|p.10565-10573|共9页
  • 作者

    Valerie A. Braz Mary D. Barkley Rebecca A. Jockusch and Patrick L. Wintrode;

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    ‡Department of Chemistry, and §Department of Physiology and Biophysics, Case Western Reserve University,10900 Euclid Avenue, Cleveland, Ohio 44106, United States, and ) Department of Chemistry,University of Toronto, Toronto, Ontario, Canada M5S 3H6;

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