Mechanism of substrate recognition by drug-resistant human immunodeficiency virus type 1 protease variants revealed by a novel structural intermediate.
Mechanism of substrate recognition by drug-resistant human immunodeficiency virus type 1 protease variants revealed by a novel structural intermediate.
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一种新型结构中间体揭示了耐药人类免疫缺陷病毒 1 型蛋白酶变体识别底物的机制。
DOI：
10.1128/jvi.80.7.3607-3616.2006
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发表时间：
2006
影响因子：
5.4
通讯作者：
Schiffer,CeliaA
中科院分区：
文献类型：
--
作者：
Prabu-Jeyabalan,Moses;Nalivaika,EllenA;Romano,Keith;Schiffer,CeliaA
人类免疫缺陷病毒1型（HIV-1）蛋白酶加工并切割Gag和Gag-Pol多聚蛋白，使病毒成熟，因此是抗病毒治疗的重要靶标。当皮瓣打开时，配体结合发生，允许进入活性部位。翼片几何形状的这种灵活性使得在底物结合中捕获和结晶结构中间体具有挑战性。在这项研究中，我们报告了两个晶体结构的两个HIV-1蛋白酶的变种结合其相应的核衣壳-p1的变体。这些结构中的每一个中的一个瓣表现出不寻常的“中间”构象。对翼片中间和翼片闭合晶体结构的分析表明，单体间翼片运动可能是异步的，并且包裹在基底的P3至P1（P3-P1）残基上的翼片可能首先闭合。这与我们的假设一致，即P3-P1区域对于底物识别至关重要。中间构象在野生型和耐药变体中都是保守的。变体之间的结构差异仅在襟翼关闭时才明显。因此，一个合理的结构模型的适应性HIV-1蛋白酶识别底物的耐药突变的存在下，已被提出。
Human immunodeficiency virus type 1 (HIV-1) protease processes and cleaves the Gag and Gag-Pol polyproteins, allowing viral maturation, and therefore is an important target for antiviral therapy. Ligand binding occurs when the flaps open, allowing access to the active site. This flexibility in flap geometry makes trapping and crystallizing structural intermediates in substrate binding challenging. In this study, we report two crystal structures of two HIV-1 protease variants bound with their corresponding nucleocapsid-p1 variant. One of the flaps in each of these structures exhibits an unusual “intermediate” conformation. Analysis of the flap-intermediate and flap-closed crystal structures reveals that the intermonomer flap movements may be asynchronous and that the flap which wraps over the P3 to P1 (P3-P1) residues of the substrate might close first. This is consistent with our hypothesis that the P3-P1 region is crucial for substrate recognition. The intermediate conformation is conserved in both the wild-type and drug-resistant variants. The structural differences between the variants are evident only when the flaps are closed. Thus, a plausible structural model for the adaptability of HIV-1 protease to recognize substrates in the presence of drug-resistant mutations has been proposed.