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6ze8

From Proteopedia

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Current revision

Crystal structure of human chitotriosidase-1 (hCHIT) catalytic domain in complex with compound OATD-01

Structural highlights

6ze8 is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.5Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 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^[4]

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

References

↑ Boot RG, Renkema GH, Strijland A, van Zonneveld AJ, Aerts JM. Cloning of a cDNA encoding chitotriosidase, a human chitinase produced by macrophages. J Biol Chem. 1995 Nov 3;270(44):26252-6. PMID:7592832
↑ Renkema GH, Boot RG, Muijsers AO, Donker-Koopman WE, Aerts JM. Purification and characterization of human chitotriosidase, a novel member of the chitinase family of proteins. J Biol Chem. 1995 Feb 3;270(5):2198-202. PMID:7836450
↑ Boot RG, Renkema GH, Verhoek M, Strijland A, Bliek J, de Meulemeester TM, Mannens MM, Aerts JM. The human chitotriosidase gene. Nature of inherited enzyme deficiency. J Biol Chem. 1998 Oct 2;273(40):25680-5. PMID:9748235
↑ 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. Discovery of OATD-01, a First-in-Class Chitinase Inhibitor as Potential New Therapeutics for Idiopathic Pulmonary Fibrosis. J Med Chem. 2020 Oct 20. doi: 10.1021/acs.jmedchem.0c01179. PMID:33078933 doi:http://dx.doi.org/10.1021/acs.jmedchem.0c01179

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6ze8"

Categories: Homo sapiens | Large Structures | Bartlomiejczak A | Napiorkowska-Gromadzka A | Nowotny M

@@ Line 3: / Line 3: @@
 <StructureSection load='6ze8' size='340' side='right'caption='[[6ze8]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6ze8]] is a 6 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=6ZE8 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6ZE8 FirstGlance]. <br>
+<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='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>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.5&#8491;</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='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='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'>[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>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6ze8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ze8 OCA], [http://pdbe.org/6ze8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ze8 RCSB], [http://www.ebi.ac.uk/pdbsum/6ze8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ze8 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://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>
+[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 ==
@@ Line 20: / Line 19: @@
 </div>
 <div class="pdbe-citations 6ze8" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Chitinase 3D structures|Chitinase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Chitinase]]
+[[Category: Homo sapiens]]
-[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Bartlomiejczak, A]]
+[[Category: Bartlomiejczak A]]
-[[Category: Napiorkowska-Gromadzka, A]]
+[[Category: Napiorkowska-Gromadzka A]]
-[[Category: Nowotny, M]]
+[[Category: Nowotny M]]
-[[Category: Chitin binding]]
-[[Category: Hydrolase]]

6ze8

From Proteopedia

Current revision

Crystal structure of human chitotriosidase-1 (hCHIT) catalytic domain in complex with compound OATD-01

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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