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PDBsum entry 6i58
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Blood clotting
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PDB id
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6i58
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References listed in PDB file
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Key reference
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Title
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Plasma kallikrein structure reveals apple domain disc rotated conformation compared to factor XI.
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Authors
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C.Li,
K.M.Voos,
M.Pathak,
G.Hall,
K.R.Mccrae,
I.Dreveny,
R.Li,
J.Emsley.
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Ref.
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J Thromb Haemost, 2019,
17,
759-770.
[DOI no: ]
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PubMed id
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Abstract
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Essentials Zymogen PK is activated to PKa and cleaves substrates kininogen and
FXII contributing to bradykinin generation. Monomeric PKa and dimeric homologue
FXI utilize the N-terminal apple domains to recruit substrates. A
high-resolution 1.3 Å structure of full-length PKa reveals an active
conformation of the protease and apple domains. The PKa protease and four-apple
domain disc organization is 180° rotated compared to FXI. SUMMARY: Background
Plasma prekallikrein (PK) and factor XI (FXI) are apple domain-containing serine
proteases that 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 Å 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 disulfide and structural differences in the apple 4
domain that prevents dimer formation in PK as opposed to FXI. Two latchlike
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° 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.
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Secondary reference #1
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Title
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Crystal structure of the factor XI zymogen reveals a pathway for transactivation.
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Authors
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E.Papagrigoriou,
P.A.Mcewan,
P.N.Walsh,
J.Emsley.
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Ref.
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Nat Struct Mol Biol, 2006,
13,
557-558.
[DOI no: ]
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PubMed id
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Figure 1.
Figure 1. FXI structure. (a) Topology of the four apple
domains is represented with the protease domain removed.
Connecting loops are colored black and the loop after A4, which
leads to the C-terminal protease domain, is colored dark blue.
(b) Topology of the FXI dimer with the protease domain colored
red and Cys321 disulfide located centrally. (c) Two close-up
views of the A4 dimer interface related by a 90° rotation.
Left, interacting side chains from one side of the dimer
interface are colored yellow, making contact with a
charge-surface representation of the other half of the interface
(blue, positive; red, negative). Right, a ribbon diagram shows a
rotated view of the A4 dimer with hydrogen bonds and
electrostatic interactions colored orange.
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Figure 2.
Figure 2. FXI activation. (a) Ribbon diagrams representing
zymogen activation by superposition of the FXIa structure
(green; PDB entry 1ZJD) and the zymogen protease domain
(yellow). The region of largest conformation change is the
activation loop comprising residues 376–370. Ile370 side chain
is colored purple in both structures. Active site Ser557 side
chain is also shown. (b) Space-filling representation of the FXI
dimer. White side chains, Arg369 and Ile370 from the activation
loop; blue side chain, Lys252 and Lys253; red side chain, Glu66.
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The above figures are
reproduced from the cited reference
with permission from Macmillan Publishers Ltd
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