|
|
| (3 intermediate revisions not shown.) |
| Line 1: |
Line 1: |
| | | | |
| | ==COMPLEMENT FACTOR D IN COMPLEX WITH A REVERSIBLE BENZOIC ACID BASED INHIBITOR== | | ==COMPLEMENT FACTOR D IN COMPLEX WITH A REVERSIBLE BENZOIC ACID BASED INHIBITOR== |
| - | <StructureSection load='5mt4' size='340' side='right' caption='[[5mt4]], [[Resolution|resolution]] 1.65Å' scene=''> | + | <StructureSection load='5mt4' size='340' side='right'caption='[[5mt4]], [[Resolution|resolution]] 1.65Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5mt4]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MT4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5MT4 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5mt4]] 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=5MT4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5MT4 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=M7O:2-[(PHENYLMETHYL)CARBAMOYLAMINO]BENZOIC+ACID'>M7O</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]] 1.65Å</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=M7O:2-[(PHENYLMETHYL)CARBAMOYLAMINO]BENZOIC+ACID'>M7O</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=5mt4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mt4 OCA], [http://pdbe.org/5mt4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mt4 RCSB], [http://www.ebi.ac.uk/pdbsum/5mt4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mt4 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=5mt4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mt4 OCA], [https://pdbe.org/5mt4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5mt4 RCSB], [https://www.ebi.ac.uk/pdbsum/5mt4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5mt4 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. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 21: |
Line 21: |
| | </div> | | </div> |
| | <div class="pdbe-citations 5mt4" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5mt4" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Complement C3 3D structures|Complement C3 3D structures]] |
| | + | *[[Complement factor 3D structures|Complement factor 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Complement factor D]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Ostermann, N]] | + | [[Category: Large Structures]] |
| - | [[Category: Sweeney, A Mac]] | + | [[Category: Mac Sweeney A]] |
| - | [[Category: Hydrolase]] | + | [[Category: Ostermann N]] |
| 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.
Publication Abstract from PubMed
Chronic dysregulation of alternative complement pathway activation has been associated with diverse clinical disorders including age-related macular degeneration and paroxysmal nocturnal hemoglobinurea. Factor D is a trypsin-like serine protease with a narrow specificity for arginine in the P1 position, which catalyzes the first enzymatic reaction of the amplification loop of the alternative pathway. In this article, we describe two hit finding approaches leading to the discovery of new chemical matter for this pivotal protease of the complement system: in silico active site mapping for hot spot identification to guide rational structure-based design and NMR screening of focused and diverse fragment libraries. The wealth of information gathered by these complementary approaches enabled the identification of ligands binding to different subpockets of the latent Factor D conformation and was instrumental for understanding the binding requirements for the generation of the first known potent noncovalent reversible Factor D inhibitors.
Structure-Based Library Design and Fragment Screening for the Identification of Reversible Complement Factor D Protease Inhibitors.,Vulpetti A, Randl S, Rudisser S, Ostermann N, Erbel P, Mac Sweeney A, Zoller T, Salem B, Gerhartz B, Cumin F, Hommel U, Dalvit C, Lorthiois E, Maibaum J J Med Chem. 2017 Feb 20. doi: 10.1021/acs.jmedchem.6b01684. PMID:28157311[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Vulpetti A, Randl S, Rudisser S, Ostermann N, Erbel P, Mac Sweeney A, Zoller T, Salem B, Gerhartz B, Cumin F, Hommel U, Dalvit C, Lorthiois E, Maibaum J. Structure-Based Library Design and Fragment Screening for the Identification of Reversible Complement Factor D Protease Inhibitors. J Med Chem. 2017 Feb 20. doi: 10.1021/acs.jmedchem.6b01684. PMID:28157311 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b01684
|
