膜受体学的基本机制:旧范式、新概念和新视角

Receptors Pub Date : 2024-03-18 DOI:10.3390/receptors3010006
Jacques Fantini
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摘要

受体学是一门研究受体的科学,是一个多层面的研究领域,可分为生物合成、膜分离、配体结合和信号转导。质膜受体将细胞与环境连接起来,并传递信号,将信号转导为生物信息。配体与受体相互作用的历史典范是锁钥模式。这种模式的前提是配体和受体双方都具有精确的三维形状,可以完美地结合在一起形成配体-受体复合物。然而,这种简单的模型存在严重的局限性,因为它在多个层面上进行了简化:(i) 没有考虑水分子和膜脂质;(ii) 并非所有配体都具有稳定的三维结构;(iii) 受体的配体结合口袋通常是灵活的,在最初的结合步骤(诱导配合机制)之后会重新排列构象和/或受配体的构象选择影响;(iv) 信号转导机制既可以是纯机械的(配体结合后诱导受体构象变化),也可以是脂质辅助的(例如,受体结合后的构象变化);(v) 信号转导机制可以是纯机械的(配体结合后诱导受体构象变化),也可以是脂质辅助的(例如,受体结合后的构象变化)。g.,如胆固醇或神经节苷脂等),或在某些情况下具有量子性质(检测气味分子)。本综述旨在挑战旧范式,提出膜受体学的新概念,考虑水分子、膜脂、静电表面电位和量子机制等关键参数的影响。
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Fundamental Mechanisms in Membrane Receptology: Old Paradigms, New Concepts and Perspectives
Receptology, the science of receptors, is a multidimensional field of research which can be dissected into biosynthesis, membrane sorting, ligand binding and signal transduction. Plasma membrane receptors connect the cells with their environment and transmit signals that are translated into biological information. The historical paradigm of ligand–receptor interactions is the lock-and-key model. This model presupposes that both partners have a precise 3D shape that perfectly fits together to form the ligand–receptor complex. However, this simple model suffers from severe limitations due to several levels of simplifications: (i) water molecules and membrane lipids are not considered; (ii) not all ligands have a stable 3D structure; (iii) the ligand-binding pocket of the receptor is often flexible and conformationally rearranged after the initial binding step (induced fit mechanism) and/or subjected to conformational selection by the ligand; (iv) there are signal transduction mechanisms which can be either purely mechanical (conformational change of the receptor induced after binding of the ligand), lipid-assisted (e.g., by raft lipids such as cholesterol or gangliosides), or in some instances of quantic nature (detection of odorant molecules). The aim of the present review is to challenge the old paradigms and present new concepts of membrane receptology that consider the impact of critical parameters such as water molecules, membrane lipids, electrostatic surface potential and quantum mechanisms.
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