5nrf: Difference between revisions

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OCA

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-'''Unreleased structure'''
-The entry 5nrf is ON HOLD
+==Crystal structure of human chitotriosidase-1 (hCHIT) catalytic domain in complex with compound 7i==
+<StructureSection load='5nrf' size='340' side='right'caption='[[5nrf]], [[Resolution|resolution]] 1.45&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5nrf]] 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=5NRF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5NRF 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]] 1.447&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=95Q:1-(3-azanyl-1~{H}-1,2,4-triazol-5-yl)-~{N}-[2-(4-chlorophenyl)ethyl]-~{N}-(phenylmethyl)piperidin-4-amine'>95Q</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=5nrf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nrf OCA], [https://pdbe.org/5nrf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5nrf RCSB], [https://www.ebi.ac.uk/pdbsum/5nrf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5nrf ProSAT]</span></td></tr>
+</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 ==
+This 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 (&gt;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.
-Authors: Mazur, M., Olczak, J., Olejniczak, S., Koralewski, R., Czestkowski, W., Jedrzejczak, A., Golab, J., Dzwonek, K., Dymek, B., Sklepkiewicz, P., Zagozdzon, A., Noonan, T., Mahboubi, K., Conway, B., Sheeler, R., Beckett, P., Hungerford, W.M., Podjarny, A., Mitschler, A., Cousido-Siah, A., Fadel, F., Golebiowski, A.
+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<ref>PMID:29283260</ref>
-Description: Crystal structure of human chitotriosidase-1 (hCHIT) catalytic domain in complex with compound 7i
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Zagozdzon, A]]
+<div class="pdbe-citations 5nrf" style="background-color:#fffaf0;"></div>
-[[Category: Dzwonek, K]]
-[[Category: Golebiowski, A]]
+==See Also==
-[[Category: Mitschler, A]]
+*[[Chitinase 3D structures|Chitinase 3D structures]]
-[[Category: Golab, J]]
+== References ==
-[[Category: Beckett, P]]
+<references/>
-[[Category: Dymek, B]]
+__TOC__
-[[Category: Olczak, J]]
+</StructureSection>
-[[Category: Sklepkiewicz, P]]
+[[Category: Homo sapiens]]
-[[Category: Fadel, F]]
+[[Category: Large Structures]]
-[[Category: Jedrzejczak, A]]
+[[Category: Beckett P]]
-[[Category: Olejniczak, S]]
+[[Category: Conway B]]
-[[Category: Podjarny, A]]
+[[Category: Cousido-Siah A]]
-[[Category: Mazur, M]]
+[[Category: Czestkowski W]]
-[[Category: Cousido-Siah, A]]
+[[Category: Dymek B]]
-[[Category: Noonan, T]]
+[[Category: Dzwonek K]]
-[[Category: Hungerford, W.M]]
+[[Category: Fadel F]]
-[[Category: Mahboubi, K]]
+[[Category: Golab J]]
-[[Category: Sheeler, R]]
+[[Category: Golebiowski A]]
-[[Category: Czestkowski, W]]
+[[Category: Hungerford WM]]
-[[Category: Koralewski, R]]
+[[Category: Jedrzejczak A]]
-[[Category: Conway, B]]
+[[Category: Koralewski R]]
+[[Category: Mahboubi K]]
+[[Category: Mazur M]]
+[[Category: Mitschler A]]
+[[Category: Noonan T]]
+[[Category: Olczak J]]
+[[Category: Olejniczak S]]
+[[Category: Podjarny A]]
+[[Category: Sheeler R]]
+[[Category: Sklepkiewicz P]]
+[[Category: Zagozdzon A]]