Ortega-López Gabriel I, Reyes-Espinosa Francisco, López-Y-López Víctor Eric, Benítez-Cardoza Claudia G
Laboratorio de Investigación Bioquímica y Biofísica Computacional, ENMH, Instituto Politécnico Nacional, Gustavo A. Madero, Ciudad de México 07320, Mexico.
Departamento de Ingeniería Ambiental, Tecnológico Nacional de México/ITS de Comalcalco, Tabasco 86650, Mexico.
Int J Mol Sci. 2025 Jul 20;26(14):6955. doi: 10.3390/ijms26146955.
Leptin is an adipocyte-derived hormone that orchestrates different physiological processes, including energy balance, thermogenesis, immune regulation, reproduction, and tissue remodeling. These effects are mediated through interaction with the CRH2 domain of the leptin receptor (Ob-R). While the structural aspects of the interaction between leptin and Ob-R have been first studied in humans and mice, comparative analyses of stability across mammalian species under physiologically relevant microenvironmental conditions remain limited. We performed a bioinformatics-driven structural, stability, and thermodynamic characterization of the leptin-CRH2 complex. This included structural homology modeling using a full-length template, interface mapping, and binding energy estimation. Additionally, we analyzed the effect of pH, ionic strength, and temperature on complex formation to mimic physiological and pathological tissue conditions to enhance clarity in the structural features and stability of the complex. Our results show that the interaction is primarily enthalpy-driven and is sensitive to temperature, ionic strength, and pH changes for all heterodimers analyzed here. The predicted binding free energy (ΔG) ranged from -10.50 to -16.81 kcal/mol across species. The integrated bioinformatic analyses suggest that subtle sequence variations influence the stability and environmental responsiveness of the complex. This study provides a molecular framework for understanding how leptin-Ob-R binding adapts across species and tissue contexts.
瘦素是一种由脂肪细胞分泌的激素，它协调不同的生理过程，包括能量平衡、产热、免疫调节、生殖和组织重塑。这些作用是通过与瘦素受体（Ob-R）的CRH2结构域相互作用介导的。虽然瘦素与Ob-R之间相互作用的结构方面最早是在人类和小鼠中进行研究的，但在生理相关微环境条件下对跨哺乳动物物种稳定性的比较分析仍然有限。我们对瘦素-CRH2复合物进行了生物信息学驱动的结构、稳定性和热力学表征。这包括使用全长模板进行结构同源建模、界面映射和结合能估计。此外，我们分析了pH、离子强度和温度对复合物形成的影响，以模拟生理和病理组织条件，从而更清楚地了解复合物的结构特征和稳定性。我们的结果表明，这种相互作用主要由焓驱动，并且对于此处分析的所有异二聚体，对温度、离子强度和pH变化敏感。预测的结合自由能（ΔG）在不同物种间范围为-10.50至-16.81千卡/摩尔。综合的生物信息学分析表明，细微的序列变异会影响复合物的稳定性和环境响应性。这项研究为理解瘦素-Ob-R结合如何在不同物种和组织环境中适应提供了一个分子框架。
