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PDBsum entry 5eod
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References listed in PDB file
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Key reference
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Title
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A novel dfp tripeptide motif interacts with the coagulation factor XI apple 2 domain.
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Authors
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S.S.Wong,
S.Østergaard,
G.Hall,
C.Li,
P.M.Williams,
H.Stennicke,
J.Emsley.
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Ref.
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Blood, 2016,
127,
2915-2923.
[DOI no: ]
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PubMed id
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Abstract
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Factor XI (FXI) is the zymogen of FXIa, which cleaves FIX in the intrinsic
pathway of coagulation. FXI is known to exist as a dimer and interacts with
multiple proteins via its 4 apple domains in the "saucer section" of
the enzyme; however, to date, no complex crystal structure has been described.
To investigate protein interactions of FXI, a large random peptide library
consisting of 10(6) to 10(7) peptides was screened for FXI binding, which
identified a series of FXI binding motifs containing the signature Asp-Phe-Pro
(DFP) tripeptide. Motifs containing this core tripeptide were found in diverse
proteins, including the known ligand high-molecular-weight kininogen (HK), as
well as the extracellular matrix proteins laminin and collagen V. To define the
binding site on FXI, we determined the crystal structure of FXI in complex with
the HK-derived peptide NPISDFPDT. This revealed the location of the DFP peptide
bound to the FXI apple 2 domain, and central to the interaction, the DFP
phenylalanine side-chain inserts into a major hydrophobic pocket in the apple 2
domain and the isoleucine occupies a flanking minor pocket. Two further
structures of FXI in complex with the laminin-derived peptide EFPDFP and a DFP
peptide from the random screen demonstrated binding in the same pocket, although
in a slightly different conformation, thus revealing some flexibility in the
molecular interactions of the FXI apple 2 domain.
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