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| | <StructureSection load='5nat' size='340' side='right'caption='[[5nat]], [[Resolution|resolution]] 1.17Å' scene=''> | | <StructureSection load='5nat' size='340' side='right'caption='[[5nat]], [[Resolution|resolution]] 1.17Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5nat]] 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=5NAT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5NAT FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5nat]] 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=5NAT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5NAT FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8RT:(2~{S})-~{N}1-(1-methylindol-3-yl)-~{N}2-[3-(trifluoromethyloxy)phenyl]pyrrolidine-1,2-dicarboxamide'>8RT</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]] 1.17Å</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=8RT:(2~{S})-~{N}1-(1-methylindol-3-yl)-~{N}2-[3-(trifluoromethyloxy)phenyl]pyrrolidine-1,2-dicarboxamide'>8RT</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5nat FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nat OCA], [http://pdbe.org/5nat PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5nat RCSB], [http://www.ebi.ac.uk/pdbsum/5nat PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5nat 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=5nat FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nat OCA], [https://pdbe.org/5nat PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5nat RCSB], [https://www.ebi.ac.uk/pdbsum/5nat PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5nat 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 == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Complement factor D]] | |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Ostermann, N]] | + | [[Category: Mac Sweeney A]] |
| - | [[Category: Sweeney, A Mac]]
| + | [[Category: Ostermann N]] |
| - | [[Category: Hydrolase]] | + | |
| 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
The highly specific S1 serine protease factor D (FD) plays a central role in the amplification of the complement alternative pathway (AP) of the innate immune system. Genetic associations in humans have implicated AP activation in age-related macular degeneration (AMD), and AP dysfunction predisposes individuals to disorders such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). The combination of structure-based hit identification and subsequent optimization of the center (S)-proline-based lead 7 has led to the discovery of noncovalent reversible and selective human factor D (FD) inhibitors with drug-like properties. The orally bioavailable compound 2 exerted excellent potency in 50% human whole blood in vitro and blocked AP activity ex vivo after oral administration to monkeys as demonstrated by inhibition of membrane attack complex (MAC) formation. Inhibitor 2 demonstrated sustained oral and ocular efficacy in a model of lipopolysaccharide (LPS)-induced systemic AP activation in mice expressing human FD.
Discovery of Highly Potent and Selective Small-Molecule Reversible Factor D Inhibitors Demonstrating Alternative Complement Pathway Inhibition in Vivo.,Lorthiois E, Anderson K, Vulpetti A, Rogel O, Cumin F, Ostermann N, Steinbacher S, Mac Sweeney A, Delgado O, Liao SM, Randl S, Rudisser S, Dussauge S, Fettis K, Kieffer L, de Erkenez A, Yang L, Hartwieg C, Argikar UA, La Bonte LR, Newton R, Kansara V, Flohr S, Hommel U, Jaffee B, Maibaum J J Med Chem. 2017 Jul 13;60(13):5717-5735. doi: 10.1021/acs.jmedchem.7b00425. Epub, 2017 Jun 30. PMID:28621538[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lorthiois E, Anderson K, Vulpetti A, Rogel O, Cumin F, Ostermann N, Steinbacher S, Mac Sweeney A, Delgado O, Liao SM, Randl S, Rudisser S, Dussauge S, Fettis K, Kieffer L, de Erkenez A, Yang L, Hartwieg C, Argikar UA, La Bonte LR, Newton R, Kansara V, Flohr S, Hommel U, Jaffee B, Maibaum J. Discovery of Highly Potent and Selective Small-Molecule Reversible Factor D Inhibitors Demonstrating Alternative Complement Pathway Inhibition in Vivo. J Med Chem. 2017 Jul 13;60(13):5717-5735. doi: 10.1021/acs.jmedchem.7b00425. Epub, 2017 Jun 30. PMID:28621538 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b00425
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