Wallace B A, Janes R W
Department of Crystallography, Birbeck College, University of London, England.
J Cardiovasc Pharmacol. 1995;26 Suppl 3:S250-3.
Several different three-dimensional structures have recently been proposed for human endothelin-1 (ET-1) based on x-ray crystallographic, NMR spectroscopic, and modeling studies. All differ considerably in the regions that are critical for receptor binding, i.e., the central loop and the C-terminal tail, which is helical in the crystal structure but not helical in any of the other structures. In this study we examined the various ET structures in light of binding and vasoactivity data available for naturally occurring isoforms and synthetic mutants of ET. These studies strongly support the crystal structure alone as being biologically relevant with respect to receptor binding. Furthermore, molecular modeling studies based on the crystal structure of ET-1 have produced models for the ET-2 and ET-3 isoforms that suggest geometric properties for the receptor selectivity pocket of the ET(A) receptor. From these studies, it appears that the crystal structure may prove useful for aiding our understanding of the nature of the receptor/ligand binding sites and for providing a basis for the design of new agonists and antagonists.
最近，基于X射线晶体学、核磁共振光谱学和建模研究，人们提出了几种不同的人内皮素-1（ET-1）三维结构。在对受体结合至关重要的区域，即中央环和C末端尾巴，所有结构都有很大差异，C末端尾巴在晶体结构中呈螺旋状，但在其他任何结构中都不是螺旋状。在本研究中，我们根据可获得的天然存在的ET同工型和合成突变体的结合及血管活性数据，对各种ET结构进行了研究。这些研究有力地支持了仅晶体结构在受体结合方面具有生物学相关性。此外，基于ET-1晶体结构的分子建模研究已经产生了ET-2和ET-3同工型的模型，这些模型揭示了ET(A)受体的受体选择性口袋的几何特性。从这些研究来看，晶体结构可能有助于我们理解受体/配体结合位点的性质，并为设计新的激动剂和拮抗剂提供基础。
