4d9r

Inhibiting Alternative Pathway Complement Activation by Targeting the Exosite on Factor DInhibiting Alternative Pathway Complement Activation by Targeting the Exosite on Factor D

Structural highlights 4d9r is a 6 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 2.42Å Ligands: Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease IGHG1_HUMAN Defects in IGHG1 are a cause of multiple myeloma (MM) [MIM:254500. MM is a malignant tumor of plasma cells usually arising in the bone marrow and characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria and anemia. Complications of multiple myeloma are bone pain, hypercalcemia, renal failure and spinal cord compression. The aberrant antibodies that are produced lead to impaired humoral immunity and patients have a high prevalence of infection. Amyloidosis may develop in some patients. Multiple myeloma is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to plasma cell leukemia. Note=A chromosomal aberration involving IGHG1 is found in multiple myeloma. Translocation t(11;14)(q13;q32) with the IgH locus. Translocation t(11;14)(q13;q32) with CCND1; translocation t(4;14)(p16.3;q32.3) with FGFR3; translocation t(6;14)(p25;q32) with IRF4. Function IGHG1_HUMAN Publication Abstract from PubMed The alternative complement pathway, by virtue of its amplifying property, has been implicated in a number of inflammatory diseases and constitutes an attractive therapeutic target. An anti-factor D Fab fragment (AFD) was generated to inhibit the alternative complement pathway in advanced dry age-related macular degeneration. AFD potently prevented factor D (FD)-mediated proteolytic activation of its macro-molecular substrate C3bB, but not proteolysis of a small synthetic substrate, indicating that AFD did not block access of substrate to the catalytic site. The crystal structures of AFD in complex with human and cynomolgus FD (at 2.4 A and 2.3 A, respectively) revealed the molecular details of the inhibitory mechanism. The structures showed that the AFD binding site included surface loops of FD that form part of the C3bB exosite. Thus, AFD inhibited FD proteolytic function by interfering with macromolecular substrate access rather than by inhibiting FD catalysis, providing the molecular basis of AFD-mediated inhibition of a rate-limiting step in the alternative complement pathway. Inhibiting alternative pathway complement activation by targeting the exosite of factor D.,Katschke KJ, Wu P, Ganesan R, Kelley RF, Mathieu MA, Hass PE, Murray J, Kirchhofer D, Wiesmann C, van Lookeren Campagne M J Biol Chem. 2012 Feb 23. PMID:22362762 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Complement factor 3D structures

spinqualitylabelsall models 4d9r, resolution 2.42Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image