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| | ==STRUCTURE OF 3,4-DICHLOROISOCOUMARIN-INHIBITED FACTOR D== | | ==STRUCTURE OF 3,4-DICHLOROISOCOUMARIN-INHIBITED FACTOR D== |
| - | <StructureSection load='1dic' size='340' side='right' caption='[[1dic]], [[Resolution|resolution]] 1.80Å' scene=''> | + | <StructureSection load='1dic' size='340' side='right'caption='[[1dic]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[1dic]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1DIC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1DIC FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[1dic]] 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=1DIC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1DIC FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DIC:3,4-DICHLOROISOCOUMARIN'>DIC</scene>, <scene name='pdbligand=O:OXYGEN+ATOM'>O</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]] 1.8Å</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Complement_factor_D Complement factor D], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.46 3.4.21.46] </span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DIC:3,4-DICHLOROISOCOUMARIN'>DIC</scene>, <scene name='pdbligand=O:OXYGEN+ATOM'>O</scene></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=1dic FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1dic OCA], [http://pdbe.org/1dic PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1dic RCSB], [http://www.ebi.ac.uk/pdbsum/1dic PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1dic ProSAT]</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=1dic FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1dic OCA], [https://pdbe.org/1dic PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1dic RCSB], [https://www.ebi.ac.uk/pdbsum/1dic PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1dic ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/CFAD_HUMAN CFAD_HUMAN]] Defects in CFD are the cause of complement factor D deficiency (CFDD) [MIM:[http://omim.org/entry/613912 613912]]. CFDD is an immunologic disorder characterized by increased susceptibility to bacterial infections, particularly Neisseria infections, due to a defect in the alternative complement pathway. | + | [https://www.uniprot.org/uniprot/CFAD_HUMAN CFAD_HUMAN] Defects in CFD are the cause of complement factor D deficiency (CFDD) [MIM:[https://omim.org/entry/613912 613912]. CFDD is an immunologic disorder characterized by increased susceptibility to bacterial infections, particularly Neisseria infections, due to a defect in the alternative complement pathway. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CFAD_HUMAN CFAD_HUMAN]] Factor D cleaves factor B when the latter is complexed with factor C3b, activating the C3bbb complex, which then becomes the C3 convertase of the alternate pathway. Its function is homologous to that of C1s in the classical pathway. | + | [https://www.uniprot.org/uniprot/CFAD_HUMAN CFAD_HUMAN] Factor D cleaves factor B when the latter is complexed with factor C3b, activating the C3bbb complex, which then becomes the C3 convertase of the alternate pathway. Its function is homologous to that of C1s in the classical pathway. |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| | Check<jmol> | | Check<jmol> |
| | <jmolCheckbox> | | <jmolCheckbox> |
| - | <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/di/1dic_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/di/1dic_consurf.spt"</scriptWhenChecked> |
| - | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
| | </jmolCheckbox> | | </jmolCheckbox> |
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| | </div> | | </div> |
| | <div class="pdbe-citations 1dic" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 1dic" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Complement factor 3D structures|Complement factor 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Complement factor D]] | |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Babu, Y S]] | + | [[Category: Large Structures]] |
| - | [[Category: Chu, N]] | + | [[Category: Babu YS]] |
| - | [[Category: Cole, L B]] | + | [[Category: Chu N]] |
| - | [[Category: Kilpatrick, J M]] | + | [[Category: Cole LB]] |
| - | [[Category: Complement]] | + | [[Category: Kilpatrick JM]] |
| - | [[Category: Factor d]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Serine protease]]
| + | |
| Structural highlights
Disease
CFAD_HUMAN Defects in CFD are the cause of complement factor D deficiency (CFDD) [MIM:613912. CFDD is an immunologic disorder characterized by increased susceptibility to bacterial infections, particularly Neisseria infections, due to a defect in the alternative complement pathway.
Function
CFAD_HUMAN Factor D cleaves factor B when the latter is complexed with factor C3b, activating the C3bbb complex, which then becomes the C3 convertase of the alternate pathway. Its function is homologous to that of C1s in the classical pathway.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Factor D (D) is a serine protease essential in the activation of the alternative complement pathway. Only a few of the common serine protease inhibitors inhibit D, binding covalently to the serine hydroxyl of the catalytic triad. 3,4-Dichloroisocoumarin (DCI) is a mechanism-based inhibitor which inhibits most serine proteases and many esterases, including D. The structure of the enzyme:inhibitor covalent adduct of D with DCI, DCI:D, to a resolution of 1.8 A is described, which represents the first structural analysis of D with a mechanism-based inhibitor. The side chain of the ring-opened DCI moiety of the protein adduct undergoes chemical modification in the buffered solution, resulting in the formation of an alpha-hydroxy acid moiety through the nucleophilic substitution of both Cl atoms. The inhibited enzyme is similar in overall structure to the native enzyme, as well as to a variety of isocoumarin-inhibited trypsin and porcine pancreatic elastase (PPE) structures, yet notable differences are observed in the active site and binding mode of these small-molecule inhibitors. One region of the active site (residues 189-195) is relatively conserved between factor D, trypsin, and elastase with respect to amino-acid sequence and to conformation. Another region (residues 214-220) reflects the amino-acid substitutions and conformational flexibility between these enzymes. The carbonyl O atom of the DCI moiety was found to be oriented away from the oxyanion hole, which greatly contributes to the stability of the DCI:D adduct. The comparisons of the active sites between native factor D, DCI-inhibited factor D, and various inhibited trypsin and elastase (PPE) molecules are providing the chemical bases directing our design of novel, small-molecule pharmaceutical agents capable of modulating the alternative complement pathway.
Structure of 3,4-dichloroisocoumarin-inhibited factor D.,Cole LB, Kilpatrick JM, Chu N, Babu YS Acta Crystallogr D Biol Crystallogr. 1998 Sep 1;54(Pt 5):711-7. PMID:9757085[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Cole LB, Kilpatrick JM, Chu N, Babu YS. Structure of 3,4-dichloroisocoumarin-inhibited factor D. Acta Crystallogr D Biol Crystallogr. 1998 Sep 1;54(Pt 5):711-7. PMID:9757085
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