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6ze8
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==Crystal structure of human chitotriosidase-1 (hCHIT) catalytic domain in complex with compound OATD-01== | ==Crystal structure of human chitotriosidase-1 (hCHIT) catalytic domain in complex with compound OATD-01== | ||
| - | <StructureSection load='6ze8' size='340' side='right'caption='[[6ze8]]' scene=''> | + | <StructureSection load='6ze8' size='340' side='right'caption='[[6ze8]], [[Resolution|resolution]] 1.50Å' 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=6ZE8 OCA]. For a <b>guided tour on the structure components</b> use [ | + | <table><tr><td colspan='2'>[[6ze8]] is a 6 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=6ZE8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZE8 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]] 1.5Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=QGB:5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine'>QGB</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=6ze8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ze8 OCA], [https://pdbe.org/6ze8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ze8 RCSB], [https://www.ebi.ac.uk/pdbsum/6ze8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ze8 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/CHIT1_HUMAN CHIT1_HUMAN] Degrades chitin, chitotriose and chitobiose. May participate in the defense against nematodes and other pathogens. Isoform 3 has no enzymatic activity.<ref>PMID:7592832</ref> <ref>PMID:7836450</ref> <ref>PMID:9748235</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Chitotriosidase (CHIT1) and acidic mammalian chitinase (AMCase) are the enzymatically active chitinases that have been implicated in the pathology of chronic lung diseases such as asthma and interstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF) and sarcoidosis. The clinical and preclinical data suggest that pharmacological inhibition of CHIT1 might represent a novel therapeutic approach in IPF. Structural modification of an advanced lead molecule 3 led to the identification of compound 9 (OATD-01), a highly active CHIT1 inhibitor with both an excellent PK profile in multiple species and selectivity against a panel of other off-targets. OATD-01 given orally once daily in a range of doses between 30 and 100 mg/kg showed significant antifibrotic efficacy in an animal model of bleomycin-induced pulmonary fibrosis. OATD-01 is the first-in-class CHIT1 inhibitor, currently completed phase 1b of clinical trials, to be a potential treatment for IPF. | ||
| + | |||
| + | Discovery of OATD-01, a First-in-Class Chitinase Inhibitor as Potential New Therapeutics for Idiopathic Pulmonary Fibrosis.,Koralewski R, Dymek B, Mazur M, Sklepkiewicz P, Olejniczak S, Czestkowski W, Matyszewski K, Andryianau G, Niedziejko P, Kowalski M, Gruza M, Borek B, Jedrzejczak K, Bartoszewicz A, Pluta E, Rymaszewska A, Kania M, Rejczak T, Piasecka S, Mlacki M, Mazurkiewicz M, Piotrowicz M, Salamon M, Zagozdzon A, Napiorkowska-Gromadzka A, Bartlomiejczak A, Mozga W, Dobrzanski P, Dzwonek K, Golab J, Nowotny M, Olczak J, Golebiowski A J Med Chem. 2020 Oct 20. doi: 10.1021/acs.jmedchem.0c01179. PMID:33078933<ref>PMID:33078933</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6ze8" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Chitinase 3D structures|Chitinase 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Bartlomiejczak A]] | [[Category: Bartlomiejczak A]] | ||
[[Category: Napiorkowska-Gromadzka A]] | [[Category: Napiorkowska-Gromadzka A]] | ||
[[Category: Nowotny M]] | [[Category: Nowotny M]] | ||
Current revision
Crystal structure of human chitotriosidase-1 (hCHIT) catalytic domain in complex with compound OATD-01
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