5tca: Difference between revisions
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<StructureSection load='5tca' size='340' side='right' caption='[[5tca]], [[Resolution|resolution]] 3.15Å' scene=''> | <StructureSection load='5tca' size='340' side='right' caption='[[5tca]], [[Resolution|resolution]] 3.15Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5tca]] is a 7 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TCA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TCA FirstGlance]. <br> | <table><tr><td colspan='2'>[[5tca]] is a 7 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TCA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TCA FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=J55:1-(2-{(2S)-2-[(6-BROMOPYRIDIN-2-YL)CARBAMOYL]-1,3-THIAZOLIDIN-3-YL}-2-OXOETHYL)-1H-PYRAZOLO[3,4-B]PYRIDINE-3-CARBOXAMIDE'>J55</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=J55:1-(2-{(2S)-2-[(6-BROMOPYRIDIN-2-YL)CARBAMOYL]-1,3-THIAZOLIDIN-3-YL}-2-OXOETHYL)-1H-PYRAZOLO[3,4-B]PYRIDINE-3-CARBOXAMIDE'>J55</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5tcc|5tcc]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5tcc|5tcc]]</td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CFD, DF, PFD ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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='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='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=5tca FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tca OCA], [http://pdbe.org/5tca PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tca RCSB], [http://www.ebi.ac.uk/pdbsum/5tca PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tca ProSAT]</span></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=5tca FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tca OCA], [http://pdbe.org/5tca PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tca RCSB], [http://www.ebi.ac.uk/pdbsum/5tca PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tca ProSAT]</span></td></tr> | ||
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</StructureSection> | </StructureSection> | ||
[[Category: Complement factor D]] | [[Category: Complement factor D]] | ||
[[Category: Human]] | |||
[[Category: Stuckey, J A]] | [[Category: Stuckey, J A]] | ||
[[Category: Hydrolase-hydrolase inhibitor complex]] | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
[[Category: Inhibitor]] | [[Category: Inhibitor]] | ||
[[Category: Serine protease]] | [[Category: Serine protease]] | ||
Revision as of 22:03, 15 November 2017
Complement Factor D inhibited with JH3Complement Factor D inhibited with JH3
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 PubMedAberrant activation of the complement system is associated with diseases, including paroxysmal nocturnal hemoglobinuria and age-related macular degeneration. Complement factor D is the rate-limiting enzyme for activating the alternative pathway in the complement system. Recent development led to a class of potent amide containing pyrrolidine derived factor D inhibitors. Here, we used biochemical enzymatic and biolayer interferometry assays to demonstrate that the amide group improves the inhibitor potency by more than 80-fold. Our crystal structures revealed buried hydrogen bond interactions are important. Molecular orbital analysis from quantum chemistry calculations dissects the chemical groups participating in these interactions. Free energy calculation supports the differential contributions of the amide group to the binding affinities of these inhibitors. Cell-based hemolysis assay confirmed these compounds inhibit factor D mediated complement activation via the alternative pathway. Our study highlights the important interactions contributing to the high potency of factor D inhibitors reported recently. Buried Hydrogen Bond Interactions Contribute to the High Potency of Complement Factor D Inhibitors.,Yang CY, Phillips JG, Stuckey JA, Bai L, Sun H, Delproposto J, Brown WC, Chinnaswamy K ACS Med Chem Lett. 2016 Sep 13;7(12):1092-1096. eCollection 2016 Dec 8. PMID:27994744[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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