Activation mechanism of endothelin ETBreceptor by endothelin-1.
Endothelin, a 21-amino-acid peptide, participates in various physiological processes, such as regulation of vascular tone, humoral homeostasis, neural crest cell development and neurotransmission. Endothelin and its G-protein-coupled receptor are involved in the development of various diseases, such as pulmonary arterial hypertension, and thus are important therapeutic targets. Here we report 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 for the isopeptide selectivity between endothelin-1 and -3. Transmembrane helices 1, 2, 6 and 7 move and envelop the entire endothelin peptide, in a virtually irreversible manner. The agonist-induced conformational changes are propagated to the receptor core and the cytoplasmic G-protein coupling interface, and probably induce conformational flexibility in TM6. A comparison with the M2 muscarinic receptor suggests a shared mechanism for signal transduction in class A G-protein-coupled receptors.
Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan.|Cellular and Structural Physiology Institute, Nagoya University, Chikusa, Nagoya 464-8601, Japan.|Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Bunkyo, Tokyo 113-0032, Japan.
Wataru
W
Shihoya
Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Bunkyo, Tokyo 113-0032, Japan.|Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.
Tomohiro
T
Nishizawa
Cellular and Structural Physiology Institute, Nagoya University, Chikusa, Nagoya 464-8601, Japan.
Akiko
A
Okuta
Cellular and Structural Physiology Institute, Nagoya University, Chikusa, Nagoya 464-8601, Japan.
Kazutoshi
K
Tani
Biomolecular Characterization Unit, RIKEN Center for Sustainable Resource Science, Wako, Saitama 351-0198, Japan.
Naoshi
N
Dohmae
Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan.|Cellular and Structural Physiology Institute, Nagoya University, Chikusa, Nagoya 464-8601, Japan.
Yoshinori
Y
Fujiyoshi
Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Bunkyo, Tokyo 113-0032, Japan.
Osamu
O
Nureki
Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan.
Tomoko
T
Doi
D000494:Allosteric Regulation; D000495:Allosteric Site; D002462:Cell Membrane / Q000378:metabolism; D018360:Crystallography, X-Ray; D019332:Endothelin-1 / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D019334:Endothelin-3 / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation; D044023:Receptor, Endothelin B / Q000819:agonists / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D043585:Receptor, Muscarinic M2 / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D013379:Substrate Specificity
D019332:Endothelin-1; D019334:Endothelin-3; D008024:Ligands; D044023:Receptor, Endothelin B; D043585:Receptor, Muscarinic M2