Icons / Logo / Facebook Created with Sketch. Icons / Logo / Google Created with Sketch. Icons / Logo / ORCID Created with Sketch. Branding/Logomark minus Citation Combined Shape Icon/Bookmark-empty Icon/Copy Icon/Collection Icon/Close Copy 7 no author result Created with Sketch. Icon/Back Created with Sketch. Match!

The X‐ray crystal structure of human endothelin 1, a polypeptide hormone regulator of blood pressure

Published on Jan 1, 2019in Acta Crystallographica Section F-structural Biology and Crystallization Communications
· DOI :10.1107/S2053230X18016011
Alexander McPherson53
Estimated H-index: 53
(UCI: University of California, Irvine),
Steven B. Larson13
Estimated H-index: 13
(UCI: University of California, Irvine)
Cite
Abstract
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 P6122, 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 P61 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 A resolution, a model containing 25 waters was refined to 1.85 A resolution with an R of 0.216 and an Rfree 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.
  • References (43)
  • Citations (1)
Cite
References43
Newest
Published on Sep 1, 2016in Nature 43.07
Wataru Shihoya3
Estimated H-index: 3
,
Tomohiro Nishizawa13
Estimated H-index: 13
+ 5 AuthorsTomoko Doi12
Estimated H-index: 12
The vasoconstricitor peptide endothelin and its G-protein-coupled receptor (GPCR) are involved in the development of various diseases, such as pulmonary arterial hypertension, so are important therapeutic targets. In this manuscript, the authors report the X-ray crystal structures of human endothelin type B receptor in the ligand-free form and in complex with the endogenous agonist endothelin-1. The structures and mutation analysis reveal the mechanism of the isopeptide selectivity between endot...
Published on Aug 1, 2016in Life Sciences 3.45
Janet J. Maguire35
Estimated H-index: 35
Biased ligands represent a new strategy for the development of more effective and better tolerated drugs. To date there has been a paucity of research exploring the potential of ligands that exhibit either G protein or β-arrestin pathway selectivity at the endothelin receptors. Re-analysis of data may allow researchers to determine whether there is existing evidence that the endogenous ET peptides or currently available agonists and antagonists exhibit pathway bias in a particular physiological ...
Philip R. Evans41
Estimated H-index: 41
(LMB: Laboratory of Molecular Biology),
Garib N. Murshudov41
Estimated H-index: 41
(LMB: Laboratory of Molecular Biology)
Following integration of the observed diffraction spots, the process of `data reduction' initially aims to determine the point-group symmetry of the data and the likely space group. This can be performed with the program POINTLESS. The scaling program then puts all the measurements on a common scale, averages measurements of symmetry-related reflections (using the symmetry determined previously) and produces many statistics that provide the first important measures of data quality. A new scaling...
Published on Oct 1, 2012in Life Sciences 3.45
Donald E. Kohan43
Estimated H-index: 43
(UofU: University of Utah),
JohnGFCleland112
Estimated H-index: 112
(Hull York Medical School)
+ 2 AuthorsMatthias Barton47
Estimated H-index: 47
(UZH: University of Zurich)
In the early 1990s, within three years of cloning of endothelin receptors, orally active endothelin receptor antagonists (ERAs) were tested in humans and the first clinical trial of ERA therapy in humans was published in 1995. ERAs were subsequently tested in clinical trials involving heart failure, pulmonary arterial hypertension, resistant arterial hypertension, stroke/subarachnoid hemorrhage and various forms of cancer. The results of most of these trials – except those for pulmonary arterial...
Published on Oct 1, 2012in Life Sciences 3.45
Janet J. Maguire35
Estimated H-index: 35
(University of Cambridge),
Rhoda E. Kuc29
Estimated H-index: 29
(University of Cambridge),
Anthony P. Davenport62
Estimated H-index: 62
(University of Cambridge)
Abstract Aims We have compared the endothelin receptor subtype affinity (K D ) and selectivity of four structural classes of antagonists (peptide, sulphonamide-based, carboxylic acid-based, myceric acid-based) in human cardiovascular tissues to determine whether these are predicted by values reported for human cloned receptors. Additionally, affinities (K B ) for these antagonists, determined in ET-1-mediated vasoconstriction assays in human blood vessels, were used to identify discrepancies bet...
Published on Mar 1, 2012in Current Opinion in Nephrology and Hypertension 3.01
Yohann Rautureau4
Estimated H-index: 4
,
Ernesto L. Schiffrin99
Estimated H-index: 99
Purpose of reviewThe purpose of this review of the vascular biology of endothelin-1 (ET-1) is the presentation of recent data including the use of endothelin-receptor antagonists for the treatment of hypertension.Recent findingsRecent discoveries regarding the pharmacology of ET-1 in the vascular wa
Philip R. Evans41
Estimated H-index: 41
(LMB: Laboratory of Molecular Biology)
This paper presents an overview of how to run the CCP4 programs for data reduction (SCALA, POINTLESS and CTRUNCATE) through the CCP4 graphical interface ccp4i and points out some issues that need to be considered, together with a few examples. It covers determination of the point-group symmetry of the diffraction data (the Laue group), which is required for the subsequent scaling step, examination of systematic absences, which in many cases will allow inference of the space group, putting multip...
Winn7
Estimated H-index: 7
(Daresbury Laboratory),
Charles Ballard3
Estimated H-index: 3
(RAL: Rutherford Appleton Laboratory)
+ 15 AuthorsAirlie J. McCoy34
Estimated H-index: 34
(University of Cambridge)
The CCP4 (Collaborative Computational Project, Number 4) software suite is a collection of programs and associated data and software libraries which can be used for macromolecular structure determination by X-ray crystallography. The suite is designed to be flexible, allowing users a number of methods of achieving their aims. The programs are from a wide variety of sources but are connected by a common infrastructure provided by standard file formats, data objects and graphical interfaces. Struc...
Garib N. Murshudov41
Estimated H-index: 41
(Ebor: University of York),
Pavol Skubák8
Estimated H-index: 8
(LEI: Leiden University)
+ 6 AuthorsA.A. Vagin8
Estimated H-index: 8
(Ebor: University of York)
This paper describes various components of the macromolecular crystallographic refinement program REFMAC5, which is distributed as part of the CCP4 suite. REFMAC5 utilizes different likelihood functions depending on the diffraction data employed (amplitudes or intensities), the presence of twinning and the availability of SAD/SIRAS experimental diffraction data. To ensure chemical and structural integrity of the refined model, REFMAC5 offers several classes of restraints and choices of model par...
Paul Emsley20
Estimated H-index: 20
(University of Oxford),
Bernhard Lohkamp11
Estimated H-index: 11
(KI: Karolinska Institutet)
+ 1 AuthorsKevin Cowtan26
Estimated H-index: 26
(Ebor: University of York)
Coot is a molecular-graphics application for model building and validation of biological macromolecules. The program displays electron-density maps and atomic models and allows model manipulations such as idealization, real-space refinement, manual rotation/translation, rigid-body fitting, ligand search, solvation, mutations, rotamers and Ramachandran idealization. Furthermore, tools are provided for model validation as well as interfaces to external programs for refinement, validation and graph...
Cited By1
Newest
Published on Apr 1, 2019in Human Immunology 2.20
Mary Carmelle Philogene3
Estimated H-index: 3
,
Tory P. Johnson1
Estimated H-index: 1
(JHUSOM: Johns Hopkins University School of Medicine)
+ 2 AuthorsNeal Fedarko
Abstract Antibodies against two G-protein coupled receptors (GPCRs), angiotensin II type 1 receptor (AT1R) and endothelin A receptor (ETAR) are among a growing number of autoantibodies that are found to be associated with allograft dysfunction. AT1R antibodies (AT1Rabs) and ETAR antibodies (ETARabs) have been shown to activate their target receptors and affect signaling pathways. Multiple single center reports have shown an association between presence of these antibodies and acute or chronic re...