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| | ==Crystal structure of the human CLR:RAMP1 extracellular domain heterodimer in complex with adrenomedullin 2/intermedin== | | ==Crystal structure of the human CLR:RAMP1 extracellular domain heterodimer in complex with adrenomedullin 2/intermedin== |
| - | <StructureSection load='6d1u' size='340' side='right' caption='[[6d1u]], [[Resolution|resolution]] 2.05Å' scene=''> | + | <StructureSection load='6d1u' size='340' side='right'caption='[[6d1u]], [[Resolution|resolution]] 2.05Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6d1u]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6D1U OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6D1U FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6d1u]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_O157:H7 Escherichia coli O157:H7] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6D1U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6D1U FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MAL:MALTOSE'>MAL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.05Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=PRD_900001:alpha-maltose'>PRD_900001</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4rwg|4rwg]], [[4rwf|4rwf]], [[5v6y|5v6y]]</td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6d1u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6d1u OCA], [https://pdbe.org/6d1u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6d1u RCSB], [https://www.ebi.ac.uk/pdbsum/6d1u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6d1u ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CALCRL, CGRPR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6d1u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6d1u OCA], [http://pdbe.org/6d1u PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6d1u RCSB], [http://www.ebi.ac.uk/pdbsum/6d1u PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6d1u ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/MALE_ECO57 MALE_ECO57]] Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides (By similarity). | + | [https://www.uniprot.org/uniprot/ADM2_HUMAN 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.<ref>PMID:14615490</ref> May play a role as physiological regulators of gastrointestinal, cardiovascular bioactivities mediated by the CALCRL/RAMPs receptor complexes. Activates the cAMP-dependent pathway.<ref>PMID:14615490</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Escherichia coli O157:H7]] |
| - | [[Category: Pioszak, A]]
| + | [[Category: Homo sapiens]] |
| - | [[Category: Roehrkasse, A]] | + | [[Category: Large Structures]] |
| - | [[Category: Amidated peptide]] | + | [[Category: Pioszak A]] |
| - | [[Category: Cgrp receptor]] | + | [[Category: Roehrkasse A]] |
| - | [[Category: Class b gpcr]] | + | |
| - | [[Category: Peptide binding protein]]
| + | |
| - | [[Category: Peptide hormone]]
| + | |
| Structural highlights
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.[1] May play a role as physiological regulators of gastrointestinal, cardiovascular bioactivities mediated by the CALCRL/RAMPs receptor complexes. Activates the cAMP-dependent pathway.[2]
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[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Roh J, Chang CL, Bhalla A, Klein C, Hsu SY. Intermedin is a calcitonin/calcitonin gene-related peptide family peptide acting through the calcitonin receptor-like receptor/receptor activity-modifying protein receptor complexes. J Biol Chem. 2004 Feb 20;279(8):7264-74. doi: 10.1074/jbc.M305332200. Epub 2003, Nov 13. PMID:14615490 doi:http://dx.doi.org/10.1074/jbc.M305332200
- ↑ Roh J, Chang CL, Bhalla A, Klein C, Hsu SY. Intermedin is a calcitonin/calcitonin gene-related peptide family peptide acting through the calcitonin receptor-like receptor/receptor activity-modifying protein receptor complexes. J Biol Chem. 2004 Feb 20;279(8):7264-74. doi: 10.1074/jbc.M305332200. Epub 2003, Nov 13. PMID:14615490 doi:http://dx.doi.org/10.1074/jbc.M305332200
- ↑ Roehrkasse AM, Booe JM, Lee SM, Warner ML, Pioszak AA. Structure-function analyses reveal a triple beta-turn receptor-bound conformation of adrenomedullin 2/intermedin and enable peptide antagonist design. J Biol Chem. 2018 Aug 23. pii: RA118.005062. doi: 10.1074/jbc.RA118.005062. PMID:30139742 doi:http://dx.doi.org/10.1074/jbc.RA118.005062
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