|
|
| (One intermediate revision not shown.) |
| Line 1: |
Line 1: |
| | | | |
| | ==Crystal Structure of Human Chymase in Complex with Fragment 6-bromo-1,3-dihydro-2H-indol-2-one== | | ==Crystal Structure of Human Chymase in Complex with Fragment 6-bromo-1,3-dihydro-2H-indol-2-one== |
| - | <StructureSection load='4k60' size='340' side='right' caption='[[4k60]], [[Resolution|resolution]] 1.50Å' scene=''> | + | <StructureSection load='4k60' size='340' side='right'caption='[[4k60]], [[Resolution|resolution]] 1.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4k60]] is a 1 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=4K60 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4K60 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4k60]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4K60 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4K60 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1P8:6-BROMO-1,3-DIHYDRO-2H-INDOL-2-ONE'>1P8</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 1.5Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3s0n|3s0n]], [[4k2y|4k2y]], [[4k5z|4k5z]], [[4k69|4k69]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1P8:6-BROMO-1,3-DIHYDRO-2H-INDOL-2-ONE'>1P8</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CMA1, CYH, CYM ([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'>[https://proteopedia.org/fgij/fg.htm?mol=4k60 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4k60 OCA], [https://pdbe.org/4k60 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4k60 RCSB], [https://www.ebi.ac.uk/pdbsum/4k60 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4k60 ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Chymase Chymase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.39 3.4.21.39] </span></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=4k60 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4k60 OCA], [http://pdbe.org/4k60 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4k60 RCSB], [http://www.ebi.ac.uk/pdbsum/4k60 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4k60 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CMA1_HUMAN CMA1_HUMAN]] Major secreted protease of mast cells with suspected roles in vasoactive peptide generation, extracellular matrix degradation, and regulation of gland secretion. | + | [https://www.uniprot.org/uniprot/CMA1_HUMAN CMA1_HUMAN] Major secreted protease of mast cells with suspected roles in vasoactive peptide generation, extracellular matrix degradation, and regulation of gland secretion. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 25: |
Line 23: |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Chymase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Large Structures]] |
| - | [[Category: Collins, B K]] | + | [[Category: Collins BK]] |
| - | [[Category: Padyana, A K]] | + | [[Category: Padyana AK]] |
| - | [[Category: Glycosylated]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Mast cell]]
| + | |
| - | [[Category: Secreted]]
| + | |
| - | [[Category: Serine protease]]
| + | |
| Structural highlights
Function
CMA1_HUMAN Major secreted protease of mast cells with suspected roles in vasoactive peptide generation, extracellular matrix degradation, and regulation of gland secretion.
Publication Abstract from PubMed
Chymase plays an important and diverse role in the homeostasis of a number of cardiovascular processes. Herein, we describe the identification of potent, selective chymase inhibitors, developed using fragment-based, structure-guided linking and optimization techniques. High-concentration biophysical screening methods followed by high-throughput crystallography identified an oxindole fragment bound to the S1 pocket of the protein exhibiting a novel interaction pattern hitherto not observed in chymase inhibitors. X-Ray crystallographic structures were used to guide the elaboration/linking of the fragment, ultimately leading to a potent inhibitor that was >100 fold selective over cathepsin G, and that mitigated a number of liabilities associated with poor physicochemical properties of the series it was derived from.
Discovery of Potent, Selective Chymase Inhibitors via Fragment Linking Strategies.,Taylor SJ, Padyana AK, Abeywardane A, Liang S, Hao MH, De Lombaert S, Proudfoot JR, Farmer BS, Li X, Collins B, Albaugh DR, Martin L, Hill-Drzewi M, Pullen SS, Takahashi H J Med Chem. 2013 May 9. PMID:23659209[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Taylor SJ, Padyana AK, Abeywardane A, Liang S, Hao MH, De Lombaert S, Proudfoot JR, Farmer BS, Li X, Collins B, Albaugh DR, Martin L, Hill-Drzewi M, Pullen SS, Takahashi H. Discovery of Potent, Selective Chymase Inhibitors via Fragment Linking Strategies. J Med Chem. 2013 May 9. PMID:23659209 doi:10.1021/jm400138z
|
