2ybu: Difference between revisions

Latest revision as of 08:12, 23 August 2023

Crystal structure of human acidic chitinase in complex with bisdionin F

Structural highlights

2ybu 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 2.25Å
Ligands:	CX9, GOL
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CHIA_HUMAN Degrades chitin and chitotriose. May participate in the defense against nematodes, fungi and other pathogens. Plays a role in T-helper cell type 2 (Th2) immune response. Contributes to the response to IL-13 and inflammation in response to IL-13. Stimulates chemokine production by pulmonary epithelial cells. Protects lung epithelial cells against apoptosis and promotes phosphorylation of AKT1. Its function in the inflammatory response and in protecting cells against apoptosis is inhibited by allosamidin, suggesting that the function of this protein depends on carbohydrate binding.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Acidic mammalian chitinase (AMCase) is produced in the lung during allergic inflammation and asthma, and inhibition of enzymatic activity has been considered as a therapeutic strategy. However, most chitinase inhibitors are nonselective, additionally inhibiting chitotriosidase activity. Here, we describe bisdionin F, a competitive AMCase inhibitor with 20-fold selectivity for AMCase over chitotriosidase, designed by utilizing the AMCase crystal structure and dicaffeine scaffold. In a murine model of allergic inflammation, bisdionin F-treatment attenuated chitinase activity and alleviated the primary features of allergic inflammation including eosinophilia. However, selective AMCase inhibition by bisdionin F also caused dramatic and unexpected neutrophilia in the lungs. This class of inhibitor will be a powerful tool to dissect the functions of mammalian chitinases in disease and represents a synthetically accessible scaffold to optimize inhibitory properties in terms of airway inflammation.

Analyzing Airway Inflammation with Chemical Biology: Dissection of Acidic Mammalian Chitinase Function with a Selective Drug-like Inhibitor.,Sutherland TE, Andersen OA, Betou M, Eggleston IM, Maizels RM, van Aalten D, Allen JE Chem Biol. 2011 May 27;18(5):569-79. PMID:21609838^[5]

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

References

↑ Boot RG, Blommaart EF, Swart E, Ghauharali-van der Vlugt K, Bijl N, Moe C, Place A, Aerts JM. Identification of a novel acidic mammalian chitinase distinct from chitotriosidase. J Biol Chem. 2001 Mar 2;276(9):6770-8. Epub 2000 Nov 20. PMID:11085997 doi:https://dx.doi.org/10.1074/jbc.M009886200
↑ Hartl D, He CH, Koller B, Da Silva CA, Homer R, Lee CG, Elias JA. Acidic mammalian chitinase is secreted via an ADAM17/epidermal growth factor receptor-dependent pathway and stimulates chemokine production by pulmonary epithelial cells. J Biol Chem. 2008 Nov 28;283(48):33472-82. doi: 10.1074/jbc.M805574200. Epub 2008, Sep 29. PMID:18824549 doi:https://dx.doi.org/10.1074/jbc.M805574200
↑ Hartl D, He CH, Koller B, Da Silva CA, Kobayashi Y, Lee CG, Flavell RA, Elias JA. Acidic mammalian chitinase regulates epithelial cell apoptosis via a chitinolytic-independent mechanism. J Immunol. 2009 Apr 15;182(8):5098-106. doi: 10.4049/jimmunol.0803446. PMID:19342690 doi:https://dx.doi.org/10.4049/jimmunol.0803446
↑ Seibold MA, Reese TA, Choudhry S, Salam MT, Beckman K, Eng C, Atakilit A, Meade K, Lenoir M, Watson HG, Thyne S, Kumar R, Weiss KB, Grammer LC, Avila P, Schleimer RP, Fahy JV, Rodriguez-Santana J, Rodriguez-Cintron W, Boot RG, Sheppard D, Gilliland FD, Locksley RM, Burchard EG. Differential enzymatic activity of common haplotypic versions of the human acidic Mammalian chitinase protein. J Biol Chem. 2009 Jul 17;284(29):19650-8. doi: 10.1074/jbc.M109.012443. Epub 2009, May 12. PMID:19435888 doi:https://dx.doi.org/10.1074/jbc.M109.012443
↑ Sutherland TE, Andersen OA, Betou M, Eggleston IM, Maizels RM, van Aalten D, Allen JE. Analyzing Airway Inflammation with Chemical Biology: Dissection of Acidic Mammalian Chitinase Function with a Selective Drug-like Inhibitor. Chem Biol. 2011 May 27;18(5):569-79. PMID:21609838 doi:10.1016/j.chembiol.2011.02.017

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OCA

[1] Boot RG, Blommaart EF, Swart E, Ghauharali-van der Vlugt K, Bijl N, Moe C, Place A, Aerts JM. Identification of a novel acidic mammalian chitinase distinct from chitotriosidase. J Biol Chem. 2001 Mar 2;276(9):6770-8. Epub 2000 Nov 20. PMID:11085997 doi:https://dx.doi.org/10.1074/jbc.M009886200

[2] Hartl D, He CH, Koller B, Da Silva CA, Homer R, Lee CG, Elias JA. Acidic mammalian chitinase is secreted via an ADAM17/epidermal growth factor receptor-dependent pathway and stimulates chemokine production by pulmonary epithelial cells. J Biol Chem. 2008 Nov 28;283(48):33472-82. doi: 10.1074/jbc.M805574200. Epub 2008, Sep 29. PMID:18824549 doi:https://dx.doi.org/10.1074/jbc.M805574200

[3] Hartl D, He CH, Koller B, Da Silva CA, Kobayashi Y, Lee CG, Flavell RA, Elias JA. Acidic mammalian chitinase regulates epithelial cell apoptosis via a chitinolytic-independent mechanism. J Immunol. 2009 Apr 15;182(8):5098-106. doi: 10.4049/jimmunol.0803446. PMID:19342690 doi:https://dx.doi.org/10.4049/jimmunol.0803446

[4] Seibold MA, Reese TA, Choudhry S, Salam MT, Beckman K, Eng C, Atakilit A, Meade K, Lenoir M, Watson HG, Thyne S, Kumar R, Weiss KB, Grammer LC, Avila P, Schleimer RP, Fahy JV, Rodriguez-Santana J, Rodriguez-Cintron W, Boot RG, Sheppard D, Gilliland FD, Locksley RM, Burchard EG. Differential enzymatic activity of common haplotypic versions of the human acidic Mammalian chitinase protein. J Biol Chem. 2009 Jul 17;284(29):19650-8. doi: 10.1074/jbc.M109.012443. Epub 2009, May 12. PMID:19435888 doi:https://dx.doi.org/10.1074/jbc.M109.012443

[5] Sutherland TE, Andersen OA, Betou M, Eggleston IM, Maizels RM, van Aalten D, Allen JE. Analyzing Airway Inflammation with Chemical Biology: Dissection of Acidic Mammalian Chitinase Function with a Selective Drug-like Inhibitor. Chem Biol. 2011 May 27;18(5):569-79. PMID:21609838 doi:10.1016/j.chembiol.2011.02.017

[1]

[2]

[3]

[4]

[5]

@@ Line 3: / Line 3: @@
 <StructureSection load='2ybu' size='340' side='right'caption='[[2ybu]], [[Resolution|resolution]] 2.25&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2ybu]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2YBU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2YBU FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2ybu]] 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=2YBU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2YBU FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CX9:3,7-DIMETHYL-1-[3-(3-METHYL-2,6-DIOXO-9H-PURIN-1-YL)PROPYL]PURINE-2,6-DIONE'>CX9</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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]] 2.25&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2ybt|2ybt]]</div></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CX9:3,7-DIMETHYL-1-[3-(3-METHYL-2,6-DIOXO-9H-PURIN-1-YL)PROPYL]PURINE-2,6-DIONE'>CX9</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Chitinase Chitinase], with EC number [https://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=2ybu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ybu OCA], [https://pdbe.org/2ybu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ybu RCSB], [https://www.ebi.ac.uk/pdbsum/2ybu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ybu ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/CHIA_HUMAN CHIA_HUMAN]] Degrades chitin and chitotriose. May participate in the defense against nematodes, fungi and other pathogens. Plays a role in T-helper cell type 2 (Th2) immune response. Contributes to the response to IL-13 and inflammation in response to IL-13. Stimulates chemokine production by pulmonary epithelial cells. Protects lung epithelial cells against apoptosis and promotes phosphorylation of AKT1. Its function in the inflammatory response and in protecting cells against apoptosis is inhibited by allosamidin, suggesting that the function of this protein depends on carbohydrate binding.<ref>PMID:11085997</ref> <ref>PMID:18824549</ref> <ref>PMID:19342690</ref> <ref>PMID:19435888</ref>
+[https://www.uniprot.org/uniprot/CHIA_HUMAN CHIA_HUMAN] Degrades chitin and chitotriose. May participate in the defense against nematodes, fungi and other pathogens. Plays a role in T-helper cell type 2 (Th2) immune response. Contributes to the response to IL-13 and inflammation in response to IL-13. Stimulates chemokine production by pulmonary epithelial cells. Protects lung epithelial cells against apoptosis and promotes phosphorylation of AKT1. Its function in the inflammatory response and in protecting cells against apoptosis is inhibited by allosamidin, suggesting that the function of this protein depends on carbohydrate binding.<ref>PMID:11085997</ref> <ref>PMID:18824549</ref> <ref>PMID:19342690</ref> <ref>PMID:19435888</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 27: / Line 26: @@
 __TOC__
 </StructureSection>
-[[Category: Chitinase]]
+[[Category: Homo sapiens]]
-[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Aalten, D van]]
+[[Category: Allen JE]]
-[[Category: Allen, J E]]
+[[Category: Andersen OA]]
-[[Category: Andersen, O A]]
+[[Category: Betou M]]
-[[Category: Betou, M]]
+[[Category: Eggleston IM]]
-[[Category: Eggleston, I M]]
+[[Category: Maizels RM]]
-[[Category: Maizels, R M]]
+[[Category: Sutherland TE]]
-[[Category: Sutherland, T E]]
+[[Category: Van Aalten D]]
-[[Category: Hydrolase]]

2ybu: Difference between revisions

Latest revision as of 08:12, 23 August 2023

Crystal structure of human acidic chitinase in complex with bisdionin F

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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