1nl0

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spinqualitylabelsall models 1nl0, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal structure of human factor IX Gla domain in complex of an inhibitory antibody, 10C12

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

The binding of Factor IX to membranes during blood coagulation is mediated, by the N-terminal gamma-carboxyglutamic acid-rich (Gla) domain, a, membrane-anchoring domain found on vitamin K-dependent blood coagulation, and regulatory proteins. Conformation-specific anti-Factor IX antibodies, are directed at the calcium-stabilized Gla domain and interfere with, Factor IX-membrane interaction. One such antibody, 10C12, recognizes the, calcium-stabilized form of the Gla domain of Factor IX. We prepared the, fully carboxylated Gla domain of Factor IX by solid phase peptide, synthesis and crystallized Factor IX-(1-47) in complex with Fab fragments, of the 10C12 antibody. The overall structure of the Gla domain in the, Factor IX-(1-47)-antibody complex at 2.2 A is similar to the structure of, the Factor IX Gla domain in the presence of calcium ions as determined by, NMR spectroscopy (Freedman, S. J., Furie, B. C., Furie, B., and Baleja, J., D. (1995) Biochemistry 34, 12126-12137) and by x-ray crystallography, (Shikamoto, Y., Morita, T., Fujimoto, Z., and Mizuno, H. (2003) J. Biol., Chem. 278, 24090-24094). The complex structure shows that the, complementarity determining region loops of the 10C12 antibody form a, hydrophobic pocket to accommodate the hydrophobic patch of the Gla domain, consisting of Leu-6, Phe-9, and Val-10. Polar interactions also play an, important role in the antibody-antigen recognition. Furthermore, the, calcium coordination network of the Factor IX Gla domain is different than, in Gla domain structures of other vitamin K-dependent proteins. We, conclude that this antibody is directed at the membrane binding site in, the omega loop of Factor IX and blocks Factor IX function by inhibiting, its interaction with membranes.

Disease

Known diseases associated with this structure: Hemophilia B OMIM:[306900], Warfarin sensitivity OMIM:[306900]

About this Structure

1NL0 is a Single protein structure of sequence from Homo sapiens with CA and SO4 as ligands. Full crystallographic information is available from OCA.

Reference

Crystal structure of the calcium-stabilized human factor IX Gla domain bound to a conformation-specific anti-factor IX antibody., Huang M, Furie BC, Furie B, J Biol Chem. 2004 Apr 2;279(14):14338-46. Epub 2004 Jan 13. PMID:14722079

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