Strader C D, Fong T M, Graziano M P, Tota M R
Department of Molecular Pharmacology and Biochemistry, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
FASEB J. 1995 Jun;9(9):745-54.
The family of G-protein-coupled receptors can be defined by their similar structural and functional characteristics. Although their primary sequences are quite diverse, these proteins share several common structural features that reflect their common mechanism of action. Mutagenesis and biophysical analysis of several of these receptors indicate that small molecule agonists and antagonists bind to a hydrophobic pocket buried in the transmembrane core of the receptor. In contrast, peptide ligands bind to both the extracellular and transmembrane domains. The mechanisms by which these peptide and small molecule agonists cause receptor activation are being explored by various approaches, but are not yet well defined. A deeper understanding of structural basis for the functional activity of this large family of receptors will have important implications for drug design in a variety of therapeutic areas.
G蛋白偶联受体家族可通过其相似的结构和功能特征来定义。尽管它们的一级序列差异很大，但这些蛋白质具有几个共同的结构特征，反映了它们共同的作用机制。对其中几种受体的诱变和生物物理分析表明，小分子激动剂和拮抗剂与受体跨膜核心中一个埋藏的疏水口袋结合。相比之下，肽配体则与细胞外和跨膜结构域都结合。目前正在通过各种方法探索这些肽和小分子激动剂导致受体激活的机制，但尚未完全明确。深入了解这一大家族受体功能活性的结构基础，将对多个治疗领域的药物设计产生重要影响。
