5tca: Difference between revisions
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==Complement Factor D inhibited with JH3== | ==Complement Factor D inhibited with JH3== | ||
<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 [ | <table><tr><td colspan='2'>[[5tca]] is a 7 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=5TCA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/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><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.15Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5tca FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tca OCA], [https://pdbe.org/5tca PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tca RCSB], [https://www.ebi.ac.uk/pdbsum/5tca PDBsum], [https://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'>[ | |||
</table> | </table> | ||
== Disease == | == Disease == | ||
[ | [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 == | ||
[ | [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;"> | |||
== Publication Abstract from PubMed == | |||
Aberrant 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<ref>PMID:27994744</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 5tca" 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/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Stuckey JA]] | ||
Latest revision as of 15:57, 4 October 2023
Complement Factor D inhibited with JH3Complement Factor D inhibited with JH3
Structural highlights
DiseaseCFAD_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. FunctionCFAD_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. See AlsoReferences
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