4rwf

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Crystal structure of the CLR:RAMP2 extracellular domain heterodimer with bound adrenomedullin

Structural highlights

4rwf is a 2 chain structure with sequence from Escherichia coli K-12 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 1.76Å
Ligands:EDO, GLC, NH2
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MALE_ECOLI Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides.RAMP2_HUMAN Transports the calcitonin gene-related peptide type 1 receptor (CALCRL) to the plasma membrane. Acts as a receptor for adrenomedullin (AM) together with CALCRL.[1] [2] 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.[3]

Publication Abstract from PubMed

Association 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[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
14 reviews cite this structure
Amylin: Pharmacology, Physiology, and Clinical Potential.
Hay et al. (2015)
13 more
31 other articles
No citations found

References

  1. ↑ Kusano S, Kukimoto-Niino M, Hino N, Ohsawa N, Okuda K, Sakamoto K, Shirouzu M, Shindo T, Yokoyama S. Structural basis for extracellular interactions between calcitonin receptor-like receptor and receptor activity-modifying protein 2 for adrenomedullin-specific binding. Protein Sci. 2012 Feb;21(2):199-210. doi: 10.1002/pro.2003. Epub 2011 Dec 28. PMID:22102369 doi:10.1002/pro.2003
  2. ↑ McLatchie LM, Fraser NJ, Main MJ, Wise A, Brown J, Thompson N, Solari R, Lee MG, Foord SM. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature. 1998 May 28;393(6683):333-9. PMID:9620797 doi:10.1038/30666
  3. ↑ Kusano S, Kukimoto-Niino M, Hino N, Ohsawa N, Okuda K, Sakamoto K, Shirouzu M, Shindo T, Yokoyama S. Structural basis for extracellular interactions between calcitonin receptor-like receptor and receptor activity-modifying protein 2 for adrenomedullin-specific binding. Protein Sci. 2012 Feb;21(2):199-210. doi: 10.1002/pro.2003. Epub 2011 Dec 28. PMID:22102369 doi:10.1002/pro.2003
  4. ↑ 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. Structural Basis for Receptor Activity-Modifying Protein-Dependent Selective Peptide Recognition by a G Protein-Coupled Receptor. Mol Cell. 2015 May 12. pii: S1097-2765(15)00300-7. doi:, 10.1016/j.molcel.2015.04.018. PMID:25982113 doi:http://dx.doi.org/10.1016/j.molcel.2015.04.018

Contents


PDB ID 4rwf

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