2oay

Crystal structure of latent human C1-inhibitor

spinqualitylabelsall models 2oay, resolution 2.35Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2oay is a 1 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 2.35Å Ligands: GOL, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease IC1_HUMAN Defects in SERPING1 are the cause of hereditary angioedema (HAE) [MIM:106100; also called hereditary angioneurotic edema (HANE). HAE is an autosomal dominant disorder characterized by episodic local subcutaneous edema and submucosal edema involving the upper respiratory and gastrointestinal tracts. HAE due to C1 esterase inhibitor deficiency is comprised of two clinically indistinguishable forms. In HAE type 1, representing 85% of patients, serum levels of C1 esterase inhibitor are less than 35% of normal. In HAE type 2, the levels are normal or elevated, but the protein is non-functional. [:] Function IC1_HUMAN Activation of the C1 complex is under control of the C1-inhibitor. It forms a proteolytically inactive stoichiometric complex with the C1r or C1s proteases. May play a potentially crucial role in regulating important physiological pathways including complement activation, blood coagulation, fibrinolysis and the generation of kinins. Very efficient inhibitor of FXIIa. Inhibits chymotrypsin and kallikrein. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed C1 inhibitor, a member of the serpin family, is a major down-regulator of inflammatory processes in blood. Genetic deficiency of C1 inhibitor results in hereditary angioedema, a dominantly inheritable, potentially lethal disease. Here we report the first crystal structure of the serpin domain of human C1 inhibitor, representing a previously unreported latent form, which explains functional consequences of several naturally occurring mutations, two of which are discussed in detail. The presented structure displays a novel conformation with a seven-stranded beta-sheet A. The unique conformation of the C-terminal six residues suggests its potential role as a barrier in the active-latent transition. On the basis of surface charge pattern, heparin affinity measurements, and docking of a heparin disaccharide, a heparin binding site is proposed in the contact area of the serpin-proteinase encounter complex. We show how polyanions change the activity of the C1 inhibitor by a novel "sandwich" mechanism, explaining earlier reaction kinetic and mutagenesis studies. These results may help to improve therapeutic C1 inhibitor preparations used in the treatment of hereditary angioedema, organ transplant rejection, and heart attack. C1 inhibitor serpin domain structure reveals the likely mechanism of heparin potentiation and conformational disease.,Beinrohr L, Harmat V, Dobo J, Lorincz Z, Gal P, Zavodszky P J Biol Chem. 2007 Jul 20;282(29):21100-9. Epub 2007 May 8. PMID:17488724 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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