5nr8: Difference between revisions
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==Crystal structure of human chitotriosidase-1 (hCHIT) catalytic domain in complex with compound 7a== | ==Crystal structure of human chitotriosidase-1 (hCHIT) catalytic domain in complex with compound 7a== | ||
<StructureSection load='5nr8' size='340' side='right' caption='[[5nr8]], [[Resolution|resolution]] 1.35Å' scene=''> | <StructureSection load='5nr8' size='340' side='right'caption='[[5nr8]], [[Resolution|resolution]] 1.35Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5nr8]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NR8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5NR8 FirstGlance]. <br> | <table><tr><td colspan='2'>[[5nr8]] 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=5NR8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5NR8 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=95N:1-(3-azanyl-1~{H}-1,2,4-triazol-5-yl)-~{N}-[2-(4-bromophenyl)ethyl]-~{N}-methyl-piperidin-4-amine'>95N</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=95N:1-(3-azanyl-1~{H}-1,2,4-triazol-5-yl)-~{N}-[2-(4-bromophenyl)ethyl]-~{N}-methyl-piperidin-4-amine'>95N</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CHIT1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Chitinase Chitinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.14 3.2.1.14] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Chitinase Chitinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.14 3.2.1.14] </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=5nr8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nr8 OCA], [http://pdbe.org/5nr8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5nr8 RCSB], [http://www.ebi.ac.uk/pdbsum/5nr8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5nr8 ProSAT]</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=5nr8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nr8 OCA], [http://pdbe.org/5nr8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5nr8 RCSB], [http://www.ebi.ac.uk/pdbsum/5nr8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5nr8 ProSAT]</span></td></tr> | ||
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</div> | </div> | ||
<div class="pdbe-citations 5nr8" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 5nr8" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Chitinase 3D structures|Chitinase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
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</StructureSection> | </StructureSection> | ||
[[Category: Chitinase]] | [[Category: Chitinase]] | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Fadel, F]] | [[Category: Fadel, F]] | ||
[[Category: Golebiowski, A]] | [[Category: Golebiowski, A]] | ||
[[Category: Podjarny, A]] | [[Category: Podjarny, A]] | ||
[[Category: Hydrolase]] | [[Category: Hydrolase]] | ||
Revision as of 09:46, 16 October 2019
Crystal structure of human chitotriosidase-1 (hCHIT) catalytic domain in complex with compound 7aCrystal structure of human chitotriosidase-1 (hCHIT) catalytic domain in complex with compound 7a
Structural highlights
Function[CHIT1_HUMAN] Degrades chitin, chitotriose and chitobiose. May participate in the defense against nematodes and other pathogens. Isoform 3 has no enzymatic activity.[1] [2] [3] Publication Abstract from PubMedThis article highlights our work toward the identification of a potent, selective, and efficacious acidic mammalian chitinase (AMCase) inhibitor. Rational design, guided by X-ray analysis of several inhibitors bound to human chitotriosidase (hCHIT1), led to the identification of compound 7f as a highly potent AMCase inhibitor (IC50 values of 14 and 19 nM against human and mouse enzyme, respectively) and selective (>150x against mCHIT1) with very good PK properties. This compound dosed once daily at 30 mg/kg po showed significant anti-inflammatory efficacy in HDM-induced allergic airway inflammation in mice, reducing inflammatory cell influx in the BALF and total IgE concentration in plasma, which correlated with decrease of chitinolytic activity. Therapeutic efficacy of compound 7f in the clinically relevant aeroallergen-induced acute asthma model in mice provides a rationale for developing AMCase inhibitor for the treatment of asthma. Targeting Acidic Mammalian chitinase Is Effective in Animal Model of Asthma.,Mazur M, Olczak J, Olejniczak S, Koralewski R, Czestkowski W, Jedrzejczak A, Golab J, Dzwonek K, Dymek B, Sklepkiewicz PL, Zagozdzon A, Noonan T, Mahboubi K, Conway B, Sheeler R, Beckett P, Hungerford WM, Podjarny A, Mitschler A, Cousido-Siah A, Fadel F, Golebiowski A J Med Chem. 2018 Feb 8;61(3):695-710. doi: 10.1021/acs.jmedchem.7b01051. Epub, 2018 Jan 11. PMID:29283260[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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