2KZA

Solution structure of ASIP(80-132, P103A, P105A, Q115Y, S124Y)

Summary for 2KZA

• Entry DOI: 10.2210/pdb2kza/pdb
• Related: 1HYK 1MR0 1Y7J 1Y7K
• NMR Information: BMRB: 17001
• Descriptor: Agouti-signaling protein (1 entity in total)
• Functional Keywords: agouti signaling protein, agouti related protein, melanocortin receptor 1, melanocortin receptor 4, mc1r, mc4r, agrp, asip, proline-switching, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 5771.92

Authors

Patel, M.P.,Cribb Fabersunne, C.S.,Yang, Y.,Kaelin, C.B.,Barsh, G.S.,Millhauser, G.L. (deposition date: 2010-06-14, release date: 2010-07-21, Last modification date: 2024-11-06)

Primary citation

Patel, M.P.,Cribb Fabersunne, C.S.,Yang, Y.K.,Kaelin, C.B.,Barsh, G.S.,Millhauser, G.L.
Loop-swapped chimeras of the agouti-related protein and the agouti signaling protein identify contacts required for melanocortin 1 receptor selectivity and antagonism.
J.Mol.Biol., 404:45-55, 2010

PubMed Abstract: Agouti-related protein (AgRP) and agouti signaling protein (ASIP) are homologs that play critical roles in energy balance and pigmentation, respectively, by functioning as antagonistic ligands at their cognate melanocortin receptors. Signaling specificity is mediated in part through receptor binding selectivity brought about by alterations in the cysteine-rich carboxy-terminal domains of the ligands. AgRP binds with high affinity to the melanocortin 3 receptor and the melanocortin 4 receptor, but not to the melanocortin 1 receptor (MC1R), whereas ASIP binds with high affinity to all three receptors. This work explores the structural basis for receptor selectivity by studying chimeric proteins developed by interchanging loops between the cysteine-rich domain of ASIP and the cysteine-rich domain of AgRP. Binding data demonstrate that melanocortin 4 receptor responds to all chimeras and is therefore highly tolerant of gross loop changes. By contrast, MC1R responds primarily to those chimeras with a sequence close to that of wild-type ASIP. Further analysis of binding and functional data suggests that the ASIP C-terminal loop (a six-amino-acid segment closed by the final disulfide bond) is essential for high-affinity MC1R binding and inverse agonism. Comparison with previously published molecular models suggests that this loop makes contact with the first extracellular loop of MC1R through a series of key hydrophobic interactions.

PubMed: 20831872
DOI: 10.1016/j.jmb.2010.08.054

Experimental method

SOLUTION NMR