8ax5 | pdb_00008ax5
Crystal structure of a CGRP receptor ectodomain heterodimer bound to macrocyclic inhibitor HTL0029881
Structural highlights
FunctionMALE_ECOLI Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides.RAMP1_HUMAN Transports the calcitonin gene-related peptide type 1 receptor (CALCRL) to the plasma membrane. Acts as a receptor for calcitonin-gene-related peptide (CGRP) together with CALCRL.[1] CALRL_HUMAN Receptor for calcitonin-gene-related peptide (CGRP) together with RAMP1 and receptor for adrenomedullin together with RAMP3 (By similarity). Receptor for adrenomedullin together with RAMP2. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.[2] Publication Abstract from PubMedThe diastereomeric macrocyclic calcitonin gene-related peptide (CGRP) antagonists HTL0029881 (3) and HTL0029882 (4), in which the stereochemistry of a spiro center is reversed, surprisingly demonstrate comparable potency. X-ray crystallographic characterization demonstrates that 3 binds to the CGRP receptor in a precedented manner but that 4 binds in an unprecedented, unexpected, and radically different manner. The observation of this phenomenon is noteworthy and may open novel avenues for CGRP receptor antagonist design. Novel Macrocyclic Antagonists of the CGRP Receptor Part 2: Stereochemical Inversion Induces an Unprecedented Binding Mode.,Southall SM, Banerjee J, Brown J, Butkovic K, Cansfield AD, Cansfield JE, Congreve MS, Cseke G, Deflorian F, Hunjadi MP, Hutinec A, Inturi TK, Rupcic R, Saxty G, Watson SP ACS Med Chem Lett. 2022 Oct 19;13(11):1776-1782. doi: , 10.1021/acsmedchemlett.2c00400. eCollection 2022 Nov 10. PMID:36385934[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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