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PDBsum entry 1zhm
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Hydrolase, blood clotting
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PDB id
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1zhm
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References listed in PDB file
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Key reference
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Title
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Mutation of surface residues to promote crystallization of activated factor XI as a complex with benzamidine: an essential step for the iterative structure-Based design of factor XI inhibitors.
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Authors
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L.Jin,
P.Pandey,
R.E.Babine,
D.T.Weaver,
S.S.Abdel-Meguid,
J.E.Strickler.
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Ref.
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Acta Crystallogr D Biol Crystallogr, 2005,
61,
1418-1425.
[DOI no: ]
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PubMed id
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Abstract
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Activated factor XI (FXIa) is a key enzyme in the amplification phase of the
blood-coagulation cascade. Thus, a selective FXIa inhibitor may have lesser
bleeding liabilities and provide a safe alternative for antithrombosis therapy
to available drugs on the market. In a previous report, the crystal structures
of the catalytic domain of FXIa (rhFXI(370-607)) in complex with various ecotin
mutants have been described. However, ecotin forms a matrix-like interaction
with rhFXI(370-607) and is impossible to displace with small-molecule
inhibitors; ecotin crystals are therefore not suitable for iterative
structure-based ligand design. In addition, rhFXI(370-607) did not crystallize
in the presence of small-molecule ligands. In order to obtain the crystal
structure of rhFXI(370-607) with a weak small-molecule ligand, namely
benzamidine, several rounds of surface-residue mutation were implemented to
promote crystal formation of rhFXI(370-607). A quadruple mutant of
rhFXI(370-607) (rhFXI(370-607)-S434A,T475A,C482S,K437A) readily crystallized in
the presence of benzamidine. The benzamidine in the preformed crystals was
easily exchanged with other FXIa small-molecule inhibitors. These crystals have
facilitated the structure-based design of small-molecule FXIa inhibitors.
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Figure 4.
Figure 4
View of the benzamidine-binding site in the
rhFXI[370-607]-S434A,T475A,C482S,K437A-benzamidine structure. Benzamidine, a sulfate
molecule in the oxyanion hole and a water molecule are shown as a ball-and-stick
representation. The residues around benzamidine are shown as a stick representation. The
hydrogen bonds between benzamidine and the protein are shown by black lines with bond
distances labeled in Å.
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Figure 5.
Figure 5
Examples of different classes of ligand soaked into
rhFXI[370-607]-S434A,T475A,C482S,K437A-benzamidine crystals. The active site of
rhFXI[370-607]-S434A,T475A,C482S,K437A is presented in a stick representation, with the
catalytic triad (Ser195, His57 and Asp102) and Asp189 labeled. The ligands are in a
ball-and-stick representation and their chemical structures are listed under each picture.
(a) A peptide-mimetic ligand covalently connects to Ser195. (b) A naphthamidine ligand
replaces benzamidine at the active site. (c) A non-basic small compound binds in the S[1]
pocket.
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The above figures are
reprinted
by permission from the IUCr:
Acta Crystallogr D Biol Crystallogr
(2005,
61,
1418-1425)
copyright 2005.
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