5tcc

Complement Factor D inhibited with JH4

spinqualitylabelsall models 5tcc, resolution 3.37Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5tcc is a 7 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.37Å Ligands: J56 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Complement C3 3D structures Complement factor 3D structures

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