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PDBsum entry 2z4e
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Blood clotting
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PDB id
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2z4e
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Contents |
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67 a.a.
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303 a.a.
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292 a.a.
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54 a.a.
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References listed in PDB file
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Key reference
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Title
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Probing the beta-Chain hole of fibrinogen with synthetic peptides that differ at their amino termini.
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Authors
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R.F.Doolittle,
L.Pandi.
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Ref.
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Biochemistry, 2007,
46,
10033-10038.
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PubMed id
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Abstract
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In a recent report, we showed that alanine can replace glycine at the amino
terminus of synthetic B-knobs that bind to human fibrin(ogen). We now report a
survey of 13 synthetic peptides with the general sequence XHRPYam, all tested
with regard to their ability to delay fibrinolysis in an in vitro system
activated by t-PA, the results being used as measures of binding affinity to the
betaC hole. Unexpectedly, some large and bulky amino acids, including methionine
and arginine, are effective binders. Amino acids that branch at the beta carbon
(valine, isoleucine, and threonine) do not bind effectively. Crystal structures
were determined for two of the peptides (GHRPYam and MHRPYam) complexed with
fibrin fragment D-dimer; the modeling of various other side chains showed
clashing in the cases of beta-carbon substituents. The two crystal structures
also showed that the enhanced binding observed with pentapeptides with
carboxyl-terminal tyrosine, compared with that of their tetrapeptide
equivalents, is attributable to an interaction between the tyrosine side chain
and a guanidino group of a nearby arginine (beta406). The equivalent position in
gamma-chains of human fibrin(ogen) is occupied by a lysine (gamma338), but in
chicken and lamprey fibrin(ogen), it is an arginine, just as occurs in beta
chains. Accordingly, the peptides GPRPam and GPRPYam, which are surrogate
A-knobs, were tested for their influence on fibrin polymerization with
fibrinogen from lamprey and humans. In lampreys, GPRPYam is a significantly
better inhibitor, but in humans, it is less effective than GPRPam, indicating
that in the lamprey system the same tyrosine-arginine interaction can also occur
in the gamma-chain setting.
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