The crystal structure of human endothelin-1 and how it relates to receptor binding

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.