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PDBsum entry 1d4p
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Hydrolase/hydrolase inhibitor
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PDB id
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1d4p
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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The crystal structure of human alpha-Thrombin complexed with ly178550, A nonpeptidyl, Active site-Directed inhibitor.
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Authors
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N.Y.Chirgadze,
D.J.Sall,
V.J.Klimkowski,
D.K.Clawson,
S.L.Briggs,
R.Hermann,
G.F.Smith,
D.S.Gifford-Moore,
J.P.Wery.
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Ref.
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Protein Sci, 1997,
6,
1412-1417.
[DOI no: ]
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PubMed id
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Abstract
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The crystal structure of human alpha-thrombin in complex with LY178550, a
nonpeptidyl, active site-directed inhibitor, has been solved to 2.07 A
resolution by the method of X-ray crystallography. The final model of the
complex has a crystallographic R-value of 21.5% (Rfree = 23.1%) with 0.014 A and
2.4 degrees standard deviation from ideal bond lengths and angles, respectively.
Well-defined electron density was observed for the inhibitor in the active site.
The inhibitor binds to the active site in an L-shaped manner, mimicking the
bound conformation of the tripeptide arginal series of thrombin inhibitors
(Chirgadze NY et al., 1992, American Crystallographic Association Meeting 20:
116 [Abstr. PB311]). The basic amidine of LY178550 forms a salt bridge with Asp
189 within the specificity pocket, while the 4-benzylpiperidine side chain
engages in a number of hydrophobic interactions at the S2 and S3 binding sites.
The inhibitor does not interact in any fashion with the active site sequence Ser
214-Gly 216, as occurs with many of the inhibitors studied previously. The
indole N-H of the inhibitor forms a hydrogen bond to the gamma-oxygen of the
catalytic serine (Ser 195).
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Figure 2.
Fig. 2. Stereo iew of 5-amidinoindole4-benzylpiperidine bond to the active site of human a-thrombin. heomittedelectrondensity
mapcorresponding to theinhibitor,whichwasued to position LY178550 intheactive site, is shown. The mapiscontouredat 1.0
level,with (2F, - a;) oefficientsat a resoluion of 2.07 A.
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Figure 4.
Fig. 4. Superposition of heX-ray crystal structures of thenonpeptidalLY178550(thickline)and tripeptide rginaLY288570 (thin
line), each ompleed with human a-thrombin. The ovelay demonstrates hat each binds in a similar manner,butwith
interaction points (see text). An -ray structure of theLY288570complexhasbeendeterminedpreviously in laboratoryat2.2 A
resolution.
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The above figures are
reprinted
from an Open Access publication published by the Protein Society:
Protein Sci
(1997,
6,
1412-1417)
copyright 1997.
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