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6zis
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==Crystal structure of a CGRP receptor ectodomain heterodimer with bound high affinity inhibitor== | ==Crystal structure of a CGRP receptor ectodomain heterodimer with bound high affinity inhibitor== | ||
| - | <StructureSection load='6zis' size='340' side='right'caption='[[6zis]]' scene=''> | + | <StructureSection load='6zis' size='340' side='right'caption='[[6zis]], [[Resolution|resolution]] 1.73Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZIS OCA]. For a <b>guided tour on the structure components</b> use [ | + | <table><tr><td colspan='2'>[[6zis]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12] 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=6ZIS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZIS FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.73Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3N6:N-{(1S)-5-AMINO-1-[(4-PYRIDIN-4-YLPIPERAZIN-1-YL)CARBONYL]PENTYL}-3,5-DIBROMO-NALPHA-{[4-(2-OXO-1,4-DIHYDROQUINAZOLIN-3(2H)-YL)PIPERIDIN-1-YL]CARBONYL}-D-TYROSINAMIDE'>3N6</scene>, <scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=PRD_900001:alpha-maltose'>PRD_900001</scene></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=6zis FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zis OCA], [https://pdbe.org/6zis PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zis RCSB], [https://www.ebi.ac.uk/pdbsum/6zis PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zis ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/RAMP1_HUMAN RAMP1_HUMAN] Transports the calcitonin gene-related peptide type 1 receptor (CALCRL) to the plasma membrane. Acts as a receptor for calcitonin-gene-related peptide (CGRP) together with CALCRL.<ref>PMID:9620797</ref> [https://www.uniprot.org/uniprot/CALRL_HUMAN 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.<ref>PMID:22102369</ref> [https://www.uniprot.org/uniprot/A0A4P1LXE0_SERSF A0A4P1LXE0_SERSF] Part of the ABC transporter complex MalEFGK involved in maltose/maltodextrin import. Binds maltose and higher maltodextrins.[RuleBase:RU365005] | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Structure-based drug design enabled the discovery of 8, HTL22562, a calcitonin gene-related peptide (CGRP) receptor antagonist. The structure of 8 complexed with the CGRP receptor was determined at a 1.6 A resolution. Compound 8 is a highly potent, selective, metabolically stable, and soluble compound suitable for a range of administration routes that have the potential to provide rapid systemic exposures with resultant high levels of receptor coverage (e.g., subcutaneous). The low lipophilicity coupled with a low anticipated clinically efficacious plasma exposure for migraine also suggests a reduced potential for hepatotoxicity. These properties have led to 8 being selected as a clinical candidate for acute treatment of migraine. | ||
| + | |||
| + | Structure-Based Drug Discovery of N-((R)-3-(7-Methyl-1H-indazol-5-yl)-1-oxo-1-(((S)-1-oxo-3-(piperidin-4-yl)-1-(4-( pyridin-4-yl)piperazin-1-yl)propan-2-yl)amino)propan-2-yl)-2'-oxo-1',2'-dihydrosp iro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazine]-1-carboxamide (HTL22562): A Calcitonin Gene-Related Peptide Receptor Antagonist for Acute Treatment of Migraine.,Bucknell SJ, Ator MA, Brown AJH, Brown J, Cansfield AD, Cansfield JE, Christopher JA, Congreve M, Cseke G, Deflorian F, Jones CR, Mason JS, O'Brien MA, Ott GR, Pickworth M, Southall SM J Med Chem. 2020 Jul 8. doi: 10.1021/acs.jmedchem.0c01003. PMID:32558564<ref>PMID:32558564</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6zis" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Maltose-binding protein 3D structures|Maltose-binding protein 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Escherichia coli K-12]] | ||
| + | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Southall SM]] | [[Category: Southall SM]] | ||
Current revision
Crystal structure of a CGRP receptor ectodomain heterodimer with bound high affinity inhibitor
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