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PDBsum entry 1ppc
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Hydrolase/hydrolase inhibitor PDB id
1ppc

 

 

 

 

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Contents
Protein chain
223 a.a. *
Ligands
MID
Metals
_CA
Waters ×147
* Residue conservation analysis
PDB id:
1ppc
Name: Hydrolase/hydrolase inhibitor
Title: Geometry of binding of the benzamidine-and arginine-based inhibitors n-alpha-(2-naphthyl-sulphonyl-glycyl)-dl-p-amidinophenylalanyl- piperidine (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
Structure: Trypsin. Chain: e. Engineered: yes
Source: Bos taurus. Cow. Organism_taxid: 9913
Resolution:
1.80Å     R-factor:   0.181    
Authors: W.Bode,D.Turk
Key ref: W.Bode et al. (1990). 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. Eur J Biochem, 193, 175-182. PubMed id: 2226434
Date:
24-Oct-91     Release date:   31-Jan-94    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00760  (TRY1_BOVIN) -  Serine protease 1 from Bos taurus
Seq:
Struc: 		246 a.a.
223 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.3.4.21.4  - trypsin.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Preferential cleavage: Arg-|-Xaa, Lys-|-Xaa.

 

 
Eur J Biochem 193:175-182 (1990)
PubMed id: 2226434  
 
 
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.
W.Bode, D.Turk, J.Stürzebecher.
 
  ABSTRACT  
 
The X-ray crystal structure of the trypsin complex formed with N alpha-(2-naphthyl-sulphonyl-glycyl)-DL-p-amidinophenylalanyl-piper idine (NAPAP) was determined with X-ray data to 0.18-nm resolution and crystallographically refined. NAPAP binds into the active site of trypsin in a quite compact form: the p-amidinophenylalanine moiety of the D-stereoisomer binds into the specificity pocket; the glycyl group is hydrogen bonded with Gly216; the naphthyl group stands perpendicular to the indole moiety of Trp215; the piperidine ring is tightly packed between this naphthyl moiety and His57; in consequence the carboxy-terminal amido bond of NAPAP is located in such a way that it is not susceptible to the active-site Ser195. 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) [Matzusaki, T., Sasaki, C., Okumura, C. & Umeyama (1989) J. Biochem. (Tokyo) 105, 949-952] were transferred in their trypsin-binding conformations to human alpha-thrombin [Bode, W., Mayr, I., Baumann, U., Huber, R., Stone, S. R. & Hofsteenge, J. (1989) EMBO J. 8. 3467 - 3475] and energy minimized. Both synthetic inhibitors fit perfectly into the much more restricted active site of thrombin. The accommodation of the S-aryl moieties in the 'aryl-binding site' and of the piperidine rings in the S2 subsite of thrombin are particularly favorable. The preference of thrombin for distinctly substituted piperidine derivatives and its generally higher (compared with trypsin) affinity for benzamidine and arginine-based inhibitors can be accounted for by these thrombin inhibitor models.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
22346912 G.Portalone (2012).
4-Meth-oxy-benzamidinium 2,6-dimeth-oxy-benzoate.
  Acta Crystallogr Sect E Struct Rep Online, 68, o268-o269.  
23284415 S.Irrera, and G.Portalone (2012).
4-Meth-oxy-benzamidinium chloride monohydrate.
  Acta Crystallogr Sect E Struct Rep Online, 68, o3083.  
19004513 G.Schneider, M.Hartenfeller, M.Reutlinger, Y.Tanrikulu, E.Proschak, and P.Schneider (2009).
Voyages to the (un)known: adaptive design of bioactive compounds.
  Trends Biotechnol, 27, 18-26.  
17372355 M.Sherawat, P.Kaur, M.Perbandt, C.Betzel, W.A.Slusarchyk, G.S.Bisacchi, C.Chang, B.L.Jacobson, H.M.Einspahr, and T.P.Singh (2007).
Structure of the complex of trypsin with a highly potent synthetic inhibitor at 0.97 A resolution.
  Acta Crystallogr D Biol Crystallogr, 63, 500-507.
PDB code: 2ayw
16370925 M.V.Serebruany, A.I.Malinin, and V.L.Serebruany (2006).
Argatroban, a direct thrombin inhibitor for heparin-induced thrombocytopaenia: present and future perspectives.
  Expert Opin Pharmacother, 7, 81-89.  
15635223 E.Toyota, H.Sekizaki, Y.U.Takahashi, K.Itoh, and K.Tanizawa (2005).
Amidino-containing Schiff base copper(II) and iron(III) chelates as a thrombin inhibitor.
  Chem Pharm Bull (Tokyo), 53, 22-26.  
15892855 W.Bode (2005).
The structure of thrombin, a chameleon-like proteinase.
  J Thromb Haemost, 3, 2379-2388.  
15322279 E.S.Henriques, N.Fonseca, and M.J.Ramos (2004).
On the modeling of snake venom serine proteinase interactions with benzamidine-based thrombin inhibitors.
  Protein Sci, 13, 2355-2369.  
12437104 M.M.Mueller, S.Sperl, J.Stürzebecher, W.Bode, and L.Moroder (2002).
(R)-3-Amidinophenylalanine-derived inhibitors of factor Xa with a novel active-site binding mode.
  Biol Chem, 383, 1185-1191.
PDB codes: 1kye 3liw
11876644 P.F.Neuenschwander, J.T.Vernon, and J.H.Morrissey (2002).
Tissue factor alters the pK(a) values of catalytically important factor VIIa residues.
  Biochemistry, 41, 3364-3371.  
12116383 S.M.Schwarzl, T.B.Tschopp, J.C.Smith, and S.Fischer (2002).
Can the calculation of ligand binding free energies be improved with continuum solvent electrostatics and an ideal-gas entropy correction?
  J Comput Chem, 23, 1143-1149.  
10716920 G.Barbato, D.O.Cicero, F.Cordier, F.Narjes, B.Gerlach, S.Sambucini, S.Grzesiek, V.G.Matassa, R.De Francesco, and R.Bazzo (2000).
Inhibitor binding induces active site stabilization of the HCV NS3 protein serine protease domain.
  EMBO J, 19, 1195-1206.
PDB code: 1dxw
10839461 S.Sperl, A.Bergner, J.Stürzebecher, V.Magdolen, W.Bode, and L.Moroder (2000).
Urethanyl-3-amidinophenylalanine derivatives as inhibitors of factor Xa. X-ray crystal structure of a trypsin/inhibitor complex and modeling studies.
  Biol Chem, 381, 321-329.  
10805774 S.Sperl, U.Jacob, N.Arroyo de Prada, J.Stürzebecher, O.G.Wilhelm, W.Bode, V.Magdolen, R.Huber, and L.Moroder (2000).
(4-aminomethyl)phenylguanidine derivatives as nonpeptidic highly selective inhibitors of human urokinase.
  Proc Natl Acad Sci U S A, 97, 5113-5118.
PDB code: 1ejn
10702294 V.Nienaber, J.Wang, D.Davidson, and J.Henkin (2000).
Re-engineering of human urokinase provides a system for structure-based drug design at high resolution and reveals a novel structural subsite.
  J Biol Chem, 275, 7239-7248.  
10446178 G.S.Coombs, M.S.Rao, A.J.Olson, P.E.Dawson, and E.L.Madison (1999).
Revisiting catalysis by chymotrypsin family serine proteases using peptide substrates and inhibitors with unnatural main chains.
  J Biol Chem, 274, 24074-24079.  
10022823 H.Jing, K.J.Macon, D.Moore, L.J.DeLucas, J.E.Volanakis, and S.V.Narayana (1999).
Structural basis of profactor D activation: from a highly flexible zymogen to a novel self-inhibited serine protease, complement factor D.
  EMBO J, 18, 804-814.
PDB code: 1fdp
10531473 R.Recacha, M.Carson, M.J.Costanzo, B.Maryanoff, L.J.DeLucas, and D.Chattopadhyay (1999).
Structure of the RWJ-51084-bovine pancreatic beta-trypsin complex at 1.8 A.
  Acta Crystallogr D Biol Crystallogr, 55, 1785-1791.
PDB code: 1qcp
10504391 T.Steinmetzer, M.Renatus, S.Künzel, A.Eichinger, W.Bode, P.Wikström, J.Hauptmann, and J.Stürzebecher (1999).
Design and evaluation of novel bivalent thrombin inhibitors based on amidinophenylalanines.
  Eur J Biochem, 265, 598-605.
PDB code: 1qur
9873562 I.Massova, P.Martin, A.Bulychev, R.Kocz, M.Doyle, B.F.Edwards, and S.Mobashery (1998).
Templates for design of inhibitors for serine proteases: application of the program DOCK to the discovery of novel inhibitors for thrombin.
  Bioorg Med Chem Lett, 8, 2463-2466.  
9836602 S.R.Presnell, G.S.Patil, C.Mura, K.M.Jude, J.M.Conley, J.A.Bertrand, C.M.Kam, J.C.Powers, and L.D.Williams (1998).
Oxyanion-mediated inhibition of serine proteases.
  Biochemistry, 37, 17068-17081.
PDB codes: 1bju 1bjv
9354617 J.J.Slon-Usakiewicz, E.Purisima, Y.Tsuda, T.Sulea, A.Pedyczak, J.Féthière, M.Cygler, and Y.Konishi (1997).
Nonpolar interactions of thrombin S' subsites with its bivalent inhibitor: methyl scan of the inhibitor linker.
  Biochemistry, 36, 13494-13502.  
9341205 S.L.Lee, R.S.Alexander, A.Smallwood, R.Trievel, L.Mersinger, P.C.Weber, and C.Kettner (1997).
New inhibitors of thrombin and other trypsin-like proteases: hydrogen bonding of an aromatic cyano group with a backbone amide of the P1 binding site replaces binding of a basic side chain.
  Biochemistry, 36, 13180-13186.
PDB code: 1auj
8605148 J.A.Bertrand, J.Oleksyszyn, C.M.Kam, B.Boduszek, S.Presnell, R.R.Plaskon, F.L.Suddath, J.C.Powers, and L.D.Williams (1996).
Inhibition of trypsin and thrombin by amino(4-amidinophenyl)methanephosphonate diphenyl ester derivatives: X-ray structures and molecular models.
  Biochemistry, 35, 3147-3155.
PDB codes: 1max 1may
8913620 J.H.Matthews, R.Krishnan, M.J.Costanzo, B.E.Maryanoff, and A.Tulinsky (1996).
Crystal structures of thrombin with thiazole-containing inhibitors: probes of the S1' binding site.
  Biophys J, 71, 2830-2839.
PDB codes: 1a4w 1tbz
8851470 W.von der Saal, R.A.Engh, A.Eichinger, B.Gabriel, R.Kucznierz, and J.Sauer (1996).
Syntheses and selective inhibitory activities of terphenyl-bisamidines for serine proteases.
  Arch Pharm (Weinheim), 329, 73-82.  
7876896 U.Egner, G.A.Hoyer, and W.D.Schleuning (1994).
Rational design of hirulog-type inhibitors of thrombin.
  J Comput Aided Mol Des, 8, 479-490.  
8296393 C.Tapparelli, R.Metternich, C.Ehrhardt, and N.S.Cook (1993).
Synthetic low-molecular weight thrombin inhibitors: molecular design and pharmacological profile.
  Trends Pharmacol Sci, 14, 366-376.  
8483337 R.A.Wiley, and D.H.Rich (1993).
Peptidomimetics derived from natural products.
  Med Res Rev, 13, 327-384.  
1310695 D.T.Hung, T.K.Vu, V.I.Wheaton, I.F.Charo, N.A.Nelken, N.Esmon, C.T.Esmon, and S.R.Coughlin (1992).
"Mirror image" antagonists of thrombin-induced platelet activation based on thrombin receptor structure.
  J Clin Invest, 89, 444-450.  
  1304379 J.Stürzebecher, U.Neumann, U.Kohnert, G.B.Kresse, and S.Fischer (1992).
Mapping of the catalytic site of CHO-t-PA and the t-PA variant BM 06.022 by synthetic inhibitors and substrates.
  Protein Sci, 1, 1007-1013.  
1528078 M.D.Walkinshaw (1992).
Protein targets for structure-based drug design.
  Med Res Rev, 12, 317-372.  
  1304349 W.Bode, D.Turk, and A.Karshikov (1992).
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.
  Protein Sci, 1, 426-471.
PDB codes: 1ai8 1aix
1765127 R.J.Breckenridge (1991).
Molecular recognition: models for drug design.
  Experientia, 47, 1148-1161.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.

 

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