4xde

Coagulation Factor XII protease domain crystal structure

spinqualitylabelsall models 4xde, resolution 2.14Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4xde is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: FLC, IPA Activity: Coagulation factor XIIa, with EC number 3.4.21.38 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum Disease [FA12_HUMAN] Congenital factor XII deficiency;Hereditary angioedema type 3. Defects in F12 are the cause of factor XII deficiency (FA12D) [MIM:234000]; also known as Hageman factor deficiency. This trait is an asymptomatic anomaly of in vitro blood coagulation. Its diagnosis is based on finding a low plasma activity of the factor in coagulating assays. It is usually only accidentally discovered through pre-operative blood tests. F12 deficiency is divided into two categories, a cross-reacting material (CRM)-negative group (negative F12 antigen detection) and a CRM-positive group (positive F12 antigen detection). Defects in F12 are the cause of hereditary angioedema type 3 (HAE3) [MIM:610618]; also known as estrogen-related HAE or hereditary angioneurotic edema with normal C1 inhibitor concentration and function. HAE is characterized by episodic local subcutaneous edema, and submucosal edema involving the upper respiratory and gastrointestinal tracts. HAE3 occurs exclusively in women and is precipitated or worsened by high estrogen levels (e.g. during pregnancy or treatment with oral contraceptives). It differs from HAE types 1 and 2 in that both concentration and function of C1 inhibitor are normal. Function [FA12_HUMAN] Factor XII is a serum glycoprotein that participates in the initiation of blood coagulation, fibrinolysis, and the generation of bradykinin and angiotensin. Prekallikrein is cleaved by factor XII to form kallikrein, which then cleaves factor XII first to alpha-factor XIIa and then trypsin cleaves it to beta-factor XIIa. Alpha-factor XIIa activates factor XI to factor XIa. Publication Abstract from PubMed BACKGROUND: Coagulation factor XII (FXII) is a serine protease important to kinin generation and blood coagulation cleaving substrates plasma kallikrein and factor XI (FXI). OBJECTIVE: To investigate FXII zymogen activation and substrate recognition we determined the crystal structure of the FXII protease domain. METHODS AND RESULTS: A series of recombinant FXII protease constructs were characterized measuring cleavage of chromogenic peptide and plasma kallikrein protein substrates. This revealed that the FXII protease construct spanning the light chain has unexpectedly weak proteolytic activity compared to beta-FXIIa which has an additional 9 amino acid remnant of the heavy chain present. Consistent with this data the crystal structure of the light chain protease reveals a zymogen conformation for active site residues Gly193 and Ser195 where the oxyanion hole is absent. The Asp194 side chain salt bridges to Arg73 is an atypical conformation of the 70-loop. In one crystal form the S1 pocket loops are partially flexible which is typical of a zymogen. In a second crystal form of the deglycosylated light chain the S1 pocket loops are ordered and a short alpha-helix in the 180-loop of the structure results in an enlarged and distorted S1 pocket with a buried conformation of residue Asp189 critical for P1 Arg substrate recognition. The FXII structures defines patches of negative charge surrounding the active site cleft which may be critical for interactions with inhibitors and substrates. CONCLUSIONS: This data provides the first structural scaffold for understanding FXII substrate recognition and zymogen activation. This article is protected by copyright. All rights reserved. Coagulation Factor XII protease domain crystal structure.,Pathak M, Wilmann P, Awford J, Li C, Fischer PM, Dreveny I, Dekker LV, Emsley J J Thromb Haemost. 2015 Jan 20. doi: 10.1111/jth.12849. PMID:25604127 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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