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The X‐ray crystal structure of human endothelin 1, a polypeptide hormone regulator of blood pressure
Author(s) -
McPherson Alexander,
Larson Steven B.
Publication year - 2019
Publication title -
acta crystallographica section f
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.572
H-Index - 37
ISSN - 2053-230X
DOI - 10.1107/s2053230x18016011
Subject(s) - regulator , hormone , endocrinology , medicine , blood pressure , endothelin receptor , endothelin 1 , chemistry , biology , biochemistry , gene , receptor
Human endothelin is a 21‐amino‐acid polypeptide, constrained by two intra‐chain disulfide bridges, that is made by endothelial cells. It is the most potent vasoconstrictor in the body and is crucially important in the regulation of blood pressure. It plays a major role in a host of medical conditions, including hypertension, diabetes, stroke and cancer. Endothelin was crystallized 28 years ago in the putative space group P 6 1 22, but the structure was never successfully solved by X‐ray diffraction. Using X‐ray diffraction data from 1992, the structure has now been solved. Assuming a unit cell belonging to space group P 6 1 and a twin fraction of 0.28, a solution emerged with two, almost identical, closely associated molecules in the asymmetric unit. Although the data extended to beyond 1.8 Å resolution, a model containing 25 waters was refined to 1.85 Å resolution with an R of 0.216 and an R free of 0.284. The disulfide‐constrained `core' of the molecule, amino‐acid residues 1–15, has a main‐chain conformation that is essentially the same as endothelin when bound to its receptor, but many side‐chain rotamers are different. The carboxy‐terminal `tail' comprising amino‐acid residues 16–21 is extended as when receptor‐bound, but it exhibits a different conformation with respect to the `core'. The dimer that comprises the asymmetric unit is maintained almost exclusively by hydrophobic interactions and may be stable in an aqueous medium.