THE RELEVANCE OF THE CRYSTAL STRUCTURE OF HUMAN ENDOTHELIN TO G-PROTEIN COUPLED RECEPTOR BINDING. B.A. Wallace and R.W. Janes, Dept. of Crystallography, Birkbeck College, University of London, London, England

The recently solved (Nature Struct. Biol. 1:311-319) crystal structure of human endothelin-1 the most potent naturally-occurring vasoconstrictor, has revealed structural features of the polypeptide that differ considerably from those found in the reported structures of endothelin as determined by NMR spectroscopy (Prot. Sci. 4:75-83). The most significant differences are in those regions important for receptor binding and specificity, namely the central loop and the C-terminal helix. Comparisons of the crystal structure with the structures of chemically-unrelated but very potent small molecule antagonists show (FEBS Lett. 374:379-383) a strong correspondence in their 3-dimensional structures. These, and correlations between its structural features and binding and activity data for a larse number of naturally-occurring and synthetic mutants strongly support the crysta1 structure as being biologically relevant with respect to binding to G-Protein coupled receptors. (Supported by a grant from the British Heart Foundation).