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PDBsum entry 1dwc
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Hydrolase/hyrolase inhibitor
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PDB id
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1dwc
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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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Crystallographic analysis at 3.0-A resolution of the binding to human thrombin of four active site-Directed inhibitors.
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Authors
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D.W.Banner,
P.Hadváry.
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Ref.
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J Biol Chem, 1991,
266,
20085-20093.
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PubMed id
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Abstract
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The mode of binding of four active-site directed inhibitors to human thrombin
has been determined by x-ray crystallographic analysis. The inhibitors studied
are benzamidine, PPACK, NAPAP, and MD-805, of which the last three are compounds
evolved specifically to inhibit thrombin. Crystal structures were determined in
the presence of both the inhibitor and the undecapeptide [des-amino
Asp55]hirudin(55-65) which binds distant from the active site. Despite having
significantly different chemical structures, NAPAP and MD-805 bind to thrombin
in a very similar "inhibitor binding mode" which is not that expected by direct
analogy with the binding of substrate. Both inhibitors bind to thrombin in a
similar way as to trypsin, but thrombin has an extra loop, the "Tyr-Pro-Pro-Trp
loop," not present in trypsin, which gives further binding interactions and is
seen to move somewhat to accommodate binding of the different inhibitors. The
fact that NAPAP and MD-805 require different stereochemistry for potent
inhibition is demonstrated, and its structural basis clarified. The wealth of
data on analogs and variants of these lead compounds is shown to be compatible
with this inhibitor binding mode.
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Secondary reference #1
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Title
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Geometry of binding of the benzamidine- And arginine-Based inhibitors n alpha-(2-Naphthyl-Sulphonyl-Glycyl)-Dl-P-Amidinophenylalanyl-Pipe ridine (napap) and (2r,4r)-4-Methyl-1-[N alpha-(3-Methyl-1,2,3,4-Tetrahydro-8- Quinolinesulphonyl)-L-Arginyl]-2-Piperidine carboxylic acid (mqpa) to human alpha-Thrombin. X-Ray crystallographic determination of the napap-Trypsin complex and modeling of napap-Thrombin and mqpa-Thrombin.
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Authors
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W.Bode,
D.Turk,
J.Stürzebecher.
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Ref.
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Eur J Biochem, 1990,
193,
175-182.
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PubMed id
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Secondary reference #2
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Title
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The refined 1.9 a crystal structure of human alpha-Thrombin: interaction with d-Phe-Pro-Arg chloromethylketone and significance of the tyr-Pro-Pro-Trp insertion segment.
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Authors
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W.Bode,
I.Mayr,
U.Baumann,
R.Huber,
S.R.Stone,
J.Hofsteenge.
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Ref.
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Embo J, 1989,
8,
3467-3475.
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PubMed id
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Secondary reference #3
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Title
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The refined 1.9-A X-Ray crystal structure of d-Phe-Pro-Arg chloromethylketone-Inhibited human alpha-Thrombin: structure analysis, Overall structure, Electrostatic properties, Detailed active-Site geometry, And structure-Function relationships.
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Authors
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W.Bode,
D.Turk,
A.Karshikov.
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Ref.
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Protein Sci, 1992,
1,
426-471.
[DOI no: ]
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PubMed id
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Figure 3.
Fig. 3. Tosyl-m-amidinophenylalanyl-piperidine (thickconnections), NAPAP (mediumconnections),and MQPA (thincon-
nections)boundtotheactivesite of humana-thrombindisplayedtogetherwiththeConnollysurface f thrombin(Turk et al.,
1991). The naphthyl/toluene/chinolyl groups of theinhibitorsinteractwiththearyl-bindingsiteofthrombin;thesidechains
ofthe m- and thep-amidinophenylalanyl residues andofthe arginylresidueenterthespecificitypocketfrom slightly differing
sites; the S2 subsiteofthrombin is occupiedtodifferentextentsbythe(partiallysubstituted)piperidinemoieties.The viewis
similartothestandard view of Figure .
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Figure 30.
Fig. 30. Luzzatiplot f thefinalthrombinmodelafterX-PLOR
refinement.
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The above figures are
reproduced from the cited reference
with permission from the Protein Society
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Secondary reference #4
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Title
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The structure of a complex of recombinant hirudin and human alpha-Thrombin.
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Authors
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T.J.Rydel,
K.G.Ravichandran,
A.Tulinsky,
W.Bode,
R.Huber,
C.Roitsch,
J.W.Fenton.
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Ref.
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Science, 1990,
249,
277-280.
[DOI no: ]
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PubMed id
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Secondary reference #5
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Title
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The interaction of thrombin with fibrinogen. A structural basis for its specificity.
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Authors
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M.T.Stubbs,
H.Oschkinat,
I.Mayr,
R.Huber,
H.Angliker,
S.R.Stone,
W.Bode.
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Ref.
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Eur J Biochem, 1992,
206,
187-195.
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PubMed id
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Secondary reference #6
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Title
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Crystal structure of the thrombin-Hirudin complex: a novel mode of serine protease inhibition.
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Authors
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M.G.Grütter,
J.P.Priestle,
J.Rahuel,
H.Grossenbacher,
W.Bode,
J.Hofsteenge,
S.R.Stone.
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Ref.
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Embo J, 1990,
9,
2361-2365.
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PubMed id
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