Energetics of the HIV gp120-CD4 binding reaction
Energetics of the HIV gp120-CD4 binding reaction
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DOI：
10.1073/pnas.97.16.9026
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发表时间：
2000-08-01
影响因子：
11.1
通讯作者：
Doyle, ML
中科院分区：
文献类型：
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作者：
Myszka, DG;Sweet, RW;Doyle, ML
HIV感染是通过细胞受体CD4和病毒的外膜糖蛋白gp120之间的选择性相互作用而启动的。我们使用分析超速离心法、滴定量热法和表面等离子体共振生物传感器分析来表征CD4-gp120相互作用的组装状态、热力学和动力学。结合热力学的大小是意想不到的；焓、熵和热容的变化大大超过了典型的蛋白质-蛋白质相互作用的描述。这些不寻常的热力学性质在完整的gp120和脱糖和截短形式的gp120蛋白中都观察到，该蛋白缺乏V1、V2和V3高变环及其N和C末端片段。结合以往的结晶学研究，热容和熵的巨大变化表明，在CD4结合时，gp120的核心发生了广泛的结构重排。CD光谱研究和结合的缓慢动力学支持这一结论。这些结果表明gp120具有相当大的构象灵活性，这可能与病毒引发感染和掩盖免疫系统保守的受体结合位点的机制有关。
HIV infection is initiated by the selective interaction between the cellular receptor CD4 and gp120, the external envelope glycoprotein of the virus. We used analytical ultracentrifugation, titration calorimetry, and surface plasmon resonance biosensor analysis to characterize the assembly state, thermodynamics, and kinetics of the CD4-gp120 interaction. The binding thermodynamics were of unexpected magnitude; changes in enthalpy, entropy, and heat capacity greatly exceeded those described for typical protein-protein interactions. These unusual thermodynamic properties were observed with both intact gp120 and a deglycosylated and truncated form of gp120 protein that lacked hypervariable loops V1, V2, and V3 and segments of its N and C termini. Together with previous crystallographic studies, the large changes in heat capacity and entropy reveal that extensive structural rearrangements occur within the core of gp120 upon CD4 binding. CD spectral studies and slow kinetics of binding support this conclusion. These results indicate considerable conformational flexibility within gp120, which may relate to viral mechanisms for triggering infection and disguising conserved receptor-binding sites from the immune system.