8AX5

Crystal structure of a CGRP receptor ectodomain heterodimer bound to macrocyclic inhibitor HTL0029881

Summary for 8AX5

• Entry DOI: 10.2210/pdb8ax5/pdb
• Related PRD ID: PRD_900001
• Descriptor: Maltose/maltodextrin-binding periplasmic protein,Receptor activity-modifying protein 1,Calcitonin gene-related peptide type 1 receptor, alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose, (1~{R},10~{R},20~{E})-12-methyl-10-[(7-methyl-2~{H}-indazol-5-yl)methyl]-15,18-dioxa-9,12,24,26-tetrazapentacyclo[20.5.2.1^{1,4}.1^{3,7}.0^{25,28}]hentriaconta-3,5,7(30),20,22,24,28-heptaene-8,11,27-trione, ... (5 entities in total)
• Functional Keywords: cgrp, cgrpr, ectodomain, ramp, macrocycle, macrocyclic, membrane protein
• Biological source: Escherichia coli K-12; More
• Total number of polymer chains: 1
• Total formula weight: 67445.71

Authors

Southall, S.M.,Watson, S.P. (deposition date: 2022-08-30, release date: 2022-12-07, Last modification date: 2024-01-31)

Primary citation

Southall, S.M.,Banerjee, J.,Brown, J.,Butkovic, K.,Cansfield, A.D.,Cansfield, J.E.,Congreve, M.S.,Cseke, G.,Deflorian, F.,Hunjadi, M.P.,Hutinec, A.,Inturi, T.K.,Rupcic, R.,Saxty, G.,Watson, S.P.
Novel Macrocyclic Antagonists of the CGRP Receptor Part 2: Stereochemical Inversion Induces an Unprecedented Binding Mode.
Acs Med.Chem.Lett., 13:1776-1782, 2022

PubMed Abstract: The diastereomeric macrocyclic calcitonin gene-related peptide (CGRP) antagonists HTL0029881 () and HTL0029882 (), in which the stereochemistry of a spiro center is reversed, surprisingly demonstrate comparable potency. X-ray crystallographic characterization demonstrates that binds to the CGRP receptor in a precedented manner but that 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.

PubMed: 36385934
DOI: 10.1021/acsmedchemlett.2c00400

Experimental method

X-RAY DIFFRACTION (2.75 Å)