6d1u

Crystal structure of the human CLR:RAMP1 extracellular domain heterodimer in complex with adrenomedullin 2/intermedin

spinqualitylabelsall models 6d1u, resolution 2.05Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6d1u is a 6 chain structure with sequence from Escherichia coli O157:H7 and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.05Å Ligands: GLC, NA, NH2, PRD_900001 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function ADM2_HUMAN May play a role as physiological regulators of gastrointestinal, cardiovascular bioactivities mediated by the CALCRL/RAMPs receptor complexes. Activates the cAMP-dependent pathway. May play a role as physiological regulators of gastrointestinal, cardiovascular bioactivities mediated by the CALCRL/RAMPs receptor complexes. Activates the cAMP-dependent pathway. Publication Abstract from PubMed The cardioprotective vasodilator peptide adrenomedullin 2/intermedin (AM2/IMD) and the related adrenomedullin (AM) and calcitonin gene-related peptide (CGRP) signal through three heterodimeric receptors comprising the calcitonin receptor-like class B G protein-coupled receptor (CLR) and a variable receptor activity modifying protein (RAMP1, -2, or -3) that determines ligand selectivity. The CGRP receptor (RAMP1:CLR) favors CGRP binding, whereas the AM1 (RAMP2:CLR) and AM2 (RAMP3:CLR) receptors favor AM binding. How AM2/IMD binds the receptors and how RAMPs modulate its binding is unknown. Here, we show that AM2/IMD binds the three purified RAMP-CLR extracellular domain (ECD) complexes with a selectivity profile that is distinct from those of CGRP and AM. AM2/IMD bound all three ECD complexes, but preferred the CGRP and AM2 receptor complexes. A 2.05 A resolution crystal structure of an AM2/IMD antagonist fragment-bound RAMP1-CLR ECD complex revealed that AM2/IMD binds the complex through a unique triple beta-turn conformation that was confirmed by peptide and receptor mutagenesis. Comparisons of the receptor-bound conformations of AM2/IMD, AM, and a high-affinity CGRP analog revealed differences that may have implications for biased signaling. Guided by the structure, enhanced-affinity AM2/IMD antagonist variants were developed, including one that discriminates the AM1 and AM2 receptors with ~40-fold difference in affinities and one stabilized by an intramolecular disulfide bond. These results reveal differences in how the three peptides engage the receptors, inform development of AM2/IMD-based pharmacological tools and therapeutics, and provide insights into RAMP modulation of receptor pharmacology. Structure-function analyses reveal a triple beta-turn receptor-bound conformation of adrenomedullin 2/intermedin and enable peptide antagonist design.,Roehrkasse AM, Booe JM, Lee SM, Warner ML, Pioszak AA J Biol Chem. 2018 Aug 23. pii: RA118.005062. doi: 10.1074/jbc.RA118.005062. PMID:30139742 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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