6zis: Difference between revisions

Latest revision as of 10:47, 23 October 2024

Crystal structure of a CGRP receptor ectodomain heterodimer with bound high affinity inhibitor

Structural highlights

Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.73Å
Ligands:	3N6, MAL, PG4
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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^[1]

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

References

↑ 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. 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. J Med Chem. 2020 Jul 8. doi: 10.1021/acs.jmedchem.0c01003. PMID:32558564 doi:https://dx.doi.org/10.1021/acs.jmedchem.0c01003

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] 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. 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. J Med Chem. 2020 Jul 8. doi: 10.1021/acs.jmedchem.0c01003. PMID:32558564 doi:https://dx.doi.org/10.1021/acs.jmedchem.0c01003

[1]

@@ Line 3: / Line 3: @@
 <StructureSection load='6zis' size='340' side='right'caption='[[6zis]], [[Resolution|resolution]] 1.73&Aring;' scene=''>
 == Structural highlights ==
-<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>
+<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 [https://proteopedia.org/fgij/fg.htm?mol=6ZIS FirstGlance]. <br>
 </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.73&#8491;</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='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=MAL:MALTOSE'>MAL</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</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>
-== 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 ==
@@ Line 26: / Line 24: @@
 __TOC__
 </StructureSection>
-[[Category: Escherichia coli K-12]]
-[[Category: Homo sapiens]]
 [[Category: Large Structures]]
 [[Category: Southall SM]]

6zis: Difference between revisions

Latest revision as of 10:47, 23 October 2024

Crystal structure of a CGRP receptor ectodomain heterodimer with bound high affinity inhibitor

Structural highlights

Publication Abstract from PubMed

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References

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