6i44

Allosteric activation of human prekallikrein by apple domain disc rotation

spinqualitylabelsall models 6i44, resolution 1.36Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6i44 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ACT, BAM, CL, FMT, GLY, GOL, MPD, NA, NAG, PE4, PEG, SER, SO4 Gene: KLKB1, KLK3 (HUMAN) Activity: Plasma kallikrein, with EC number 3.4.21.34 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [KLKB1_HUMAN] Defects in KLKB1 are the cause of prekallikrein deficiency (PKK deficiency) [MIM:612423]; also known as Fletcher factor deficiency. This disorder is a blood coagulation defect. Function [KLKB1_HUMAN] The enzyme cleaves Lys-Arg and Arg-Ser bonds. It activates, in a reciprocal reaction, factor XII after its binding to a negatively charged surface. It also releases bradykinin from HMW kininogen and may also play a role in the renin-angiotensin system by converting prorenin into renin. Publication Abstract from PubMed BACKGROUND: Plasma prekallikrein (PK) and Factor XI (FXI) are apple domain containing serine proteases which when activated to PKa and FXIa cleave substrates kininogen, Factor XII and Factor IX respectively directing plasma coagulation, bradykinin release, inflammation and thrombosis pathways. OBJECTIVE: To investigate the three-dimensional structure of full-length PKa and perform a comparison with FXI. METHODS: A series of recombinant full-length PKa and FXI constructs and variants were developed and the crystal structures determined. RESULTS AND CONCLUSIONS: A 1.3 A structure of full-length PKa reveals the protease domain positioned above a disc-shaped assemblage of four apple domains in an active conformation. A comparison with the homologous FXI structure reveals the intramolecular disulphide and structural differences in the apple 4 domain that prevents dimer formation in PKa as opposed to FXI. Two latch-like loops (LL1 and LL2) extend from the PKa protease domain to form interactions with the apple 1 and apple 3 domains respectively. A major unexpected difference in the PKa structure compared to FXI is the 180 masculine disc rotation of the apple domains relative to the protease domain. This results in a switched configuration of the latch loops such that LL2 interacts and buries portions of the apple 3 domain in the FXI zymogen whereas in PKa LL2 interacts with the apple 1 domain. Hydrogen-deuterium exchange mass spectrometry on plasma purified human PK and PKa determined that regions of the apple 3 domain have increased surface exposure in PKa compared to the zymogen PK suggesting conformational change upon activation. This article is protected by copyright. All rights reserved. Plasma Kallikrein Structure Reveals Apple Domain Disc Rotated Conformation Compared to Factor XI.,Li C, Voos KM, Pathak M, Hall G, McCrae KR, Dreveny I, Li R, Emsley J J Thromb Haemost. 2019 Feb 23. doi: 10.1111/jth.14418. PMID:30801944 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Kallikrein 3D structures

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