4rwf
From Proteopedia
Crystal structure of the CLR:RAMP2 extracellular domain heterodimer with bound adrenomedullin
Structural highlights
Function[MALE_ECOLI] Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides. [ADML_HUMAN] AM and PAMP are potent hypotensive and vasodilatator agents. Numerous actions have been reported most related to the physiologic control of fluid and electrolyte homeostasis. In the kidney, am is diuretic and natriuretic, and both am and pamp inhibit aldosterone secretion by direct adrenal actions. In pituitary gland, both peptides at physiologically relevant doses inhibit basal ACTH secretion. Both peptides appear to act in brain and pituitary gland to facilitate the loss of plasma volume, actions which complement their hypotensive effects in blood vessels. Publication Abstract from PubMedAssociation of receptor activity-modifying proteins (RAMP1-3) with the G protein-coupled receptor (GPCR) calcitonin receptor-like receptor (CLR) enables selective recognition of the peptides calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) that have diverse functions in the cardiovascular and lymphatic systems. How peptides selectively bind GPCR:RAMP complexes is unknown. We report crystal structures of CGRP analog-bound CLR:RAMP1 and AM-bound CLR:RAMP2 extracellular domain heterodimers at 2.5 and 1.8 A resolutions, respectively. The peptides similarly occupy a shared binding site on CLR with conformations characterized by a beta-turn structure near their C termini rather than the alpha-helical structure common to peptides that bind related GPCRs. The RAMPs augment the binding site with distinct contacts to the variable C-terminal peptide residues and elicit subtly different CLR conformations. The structures and accompanying pharmacology data reveal how a class of accessory membrane proteins modulate ligand binding of a GPCR and may inform drug development targeting CLR:RAMP complexes. Structural Basis for Receptor Activity-Modifying Protein-Dependent Selective Peptide Recognition by a G Protein-Coupled Receptor.,Booe JM, Walker CS, Barwell J, Kuteyi G, Simms J, Jamaluddin MA, Warner ML, Bill RM, Harris PW, Brimble MA, Poyner DR, Hay DL, Pioszak AA Mol Cell. 2015 May 12. pii: S1097-2765(15)00300-7. doi:, 10.1016/j.molcel.2015.04.018. PMID:25982113[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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