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PDBsum entry 6gch

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Hydrolase (serine proteinase) PDB id
6gch
Jmol
Contents
Protein chains
11 a.a.
131 a.a. *
95 a.a. *
Ligands
APF
Waters ×188
* Residue conservation analysis
PDB id:
6gch
Name: Hydrolase (serine proteinase)
Title: Structure of chymotrypsin- Trifluoromethyl ketone inhibitor complexes. Comparison of slowly and rapidly equilibrating inhibitors
Structure: Gamma-chymotrypsin a. Chain: e. Gamma-chymotrypsin a. Chain: f. Gamma-chymotrypsin a. Chain: g. Ec: 3.4.21.1
Source: Bos taurus. Cattle. Organism_taxid: 9913. Organism_taxid: 9913
Biol. unit: Trimer (from PQS)
Resolution:
2.10Å     R-factor:   0.180    
Authors: K.Brady,A.Wei,D.Ringe,R.H.Abeles
Key ref:
K.Brady et al. (1990). Structure of chymotrypsin-trifluoromethyl ketone inhibitor complexes: comparison of slowly and rapidly equilibrating inhibitors. Biochemistry, 29, 7600-7607. PubMed id: 2271520 DOI: 10.1021/bi00485a009
Date:
06-Apr-90     Release date:   15-Oct-90    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00766  (CTRA_BOVIN) -  Chymotrypsinogen A
Seq:
Struc:
245 a.a.
11 a.a.
Protein chain
Pfam   ArchSchema ?
P00766  (CTRA_BOVIN) -  Chymotrypsinogen A
Seq:
Struc:
245 a.a.
131 a.a.
Protein chain
Pfam   ArchSchema ?
P00766  (CTRA_BOVIN) -  Chymotrypsinogen A
Seq:
Struc:
245 a.a.
95 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains E, F, G: E.C.3.4.21.1  - Chymotrypsin.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Preferential cleavage: Tyr-|-Xaa, Trp-|-Xaa, Phe-|-Xaa, Leu-|-Xaa.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     proteolysis   1 term 
  Biochemical function     catalytic activity     2 terms  

 

 
DOI no: 10.1021/bi00485a009 Biochemistry 29:7600-7607 (1990)
PubMed id: 2271520  
 
 
Structure of chymotrypsin-trifluoromethyl ketone inhibitor complexes: comparison of slowly and rapidly equilibrating inhibitors.
K.Brady, A.Z.Wei, D.Ringe, R.H.Abeles.
 
  ABSTRACT  
 
The peptidyl trifluoromethyl ketones Ac-Phe-CF3 (1) and Ac-Leu-Phe-CF3 (2) are inhibitors of chymotrypsin. They differ in Ki (20 and 2 microM, respectively) as well as in their kinetics of association with chymotrypsin in that 1 is rapidly equilibrating, with an association rate too fast to be observed by steady-state techniques, while 2 is "slow binding", as defined by Morrison and Walsh [Morrison, J. F., & Walsh, C. T. (1988) Adv. Enzymol. Relat. Areas Mol. Biol. 61, 202], with a second-order association rate constant of 750 M-1 s-1 at pH 7.0 [Imperiali, B., & Abeles, R. (1986) Biochemistry 25, 3760]. The crystallographic structures of the complexes of gamma-chymotrypsin with inhibitors 1 and 2 have been determined in order to establish whether structural or conformational differences can be found which account for different kinetic and thermodynamic properties of the two inhibitors. In both complexes, the active-site Ser 195 hydroxyl forms a covalent hemiketal adduct with the trifluoromethyl ketone moiety of the inhibitor. In both complexes, the trifluoromethyl group is partially immobilized, but differences are observed in the degree of interaction of fluorine atoms with the active-site His 57 imidazole ring, with amide nitrogen NH 193, and with other portions of the inhibitor molecule. The enhanced potency of Ac-Leu-Phe-CF3 relative to Ac-Phe-CF3 is accounted for by van der Waals interactions of the leucine side chain of the inhibitor with His 57 and Ile 99 side chains and by a hydrogen bond of the acetyl terminus with amide NH 216 of the enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
19549826 E.Zakharova, M.P.Horvath, and D.P.Goldenberg (2009).
Structure of a serine protease poised to resynthesize a peptide bond.
  Proc Natl Acad Sci U S A, 106, 11034-11039.
PDB codes: 3fp6 3fp7 3fp8
19089976 T.Rungrotmongkol, P.Decha, P.Sompornpisut, M.Malaisree, P.Intharathep, N.Nunthaboot, T.Udommaneethanakit, O.Aruksakunwong, and S.Hannongbua (2009).
Combined QM/MM mechanistic study of the acylation process in furin complexed with the H5N1 avian influenza virus hemagglutinin's cleavage site.
  Proteins, 76, 62-71.  
17805946 B.Jelinek, G.Katona, K.Fodor, I.Venekei, and L.Gráf (2008).
The crystal structure of a trypsin-like mutant chymotrypsin: the role of position 226 in the activity and specificity of S189D chymotrypsin.
  Protein J, 27, 79-87.
PDB code: 2jet
18023188 C.E.Wheelock, K.Nishi, A.Ying, P.D.Jones, M.E.Colvin, M.M.Olmstead, and B.D.Hammock (2008).
Influence of sulfur oxidation state and steric bulk upon trifluoromethyl ketone (TFK) binding kinetics to carboxylesterases and fatty acid amide hydrolase (FAAH).
  Bioorg Med Chem, 16, 2114-2130.  
  19727327 D.B.Berkowitz, K.R.Karukurichi, R.de la Salud-Bea, D.L.Nelson, and C.D.McCune (2008).
Use of Fluorinated Functionality in Enzyme Inhibitor Development: Mechanistic and Analytical Advantages.
  J Fluor Chem, 129, 731-742.  
18498103 D.C.Bas, D.M.Rogers, and J.H.Jensen (2008).
Very fast prediction and rationalization of pKa values for protein-ligand complexes.
  Proteins, 73, 765-783.  
17912756 M.Shokhen, N.Khazanov, and A.Albeck (2008).
Screening of the active site from water by the incoming ligand triggers catalysis and inhibition in serine proteases.
  Proteins, 70, 1578-1587.  
17469803 A.Moulin, J.H.Bell, R.F.Pratt, and D.Ringe (2007).
Inhibition of chymotrypsin by a complex of ortho-vanadate and benzohydroxamic acid: structure of the inert complex and its mechanistic interpretation.
  Biochemistry, 46, 5982-5990.
PDB code: 2p8o
17213185 E.Spink, S.Cosgrove, L.Rogers, C.Hewage, and J.P.Malthouse (2007).
13C and 1H NMR studies of ionizations and hydrogen bonding in chymotrypsin-glyoxal inhibitor complexes.
  J Biol Chem, 282, 7852-7861.  
17600794 M.Shokhen, N.Khazanov, and A.Albeck (2007).
The cooperative effect between active site ionized groups and water desolvation controls the alteration of acid/base catalysis in serine proteases.
  Chembiochem, 8, 1416-1421.  
16754679 B.Liu, C.J.Schofield, and R.C.Wilmouth (2006).
Structural analyses on intermediates in serine protease catalysis.
  J Biol Chem, 281, 24024-24035.
PDB codes: 2bb4 2bd2 2bd3 2bd4 2bd5 2bd7 2bd8 2bd9 2bda 2bdb 2bdc 2h1u
15103633 C.N.Schutz, and A.Warshel (2004).
The low barrier hydrogen bond (LBHB) proposal revisited: the case of the Asp... His pair in serine proteases.
  Proteins, 55, 711-723.  
14747995 M.Shokhen, and A.Albeck (2004).
Is there a weak H-bond --> LBHB transition on tetrahedral complex formation in serine proteases?
  Proteins, 54, 468-477.  
12081470 G.G.Hammes (2002).
Multiple conformational changes in enzyme catalysis.
  Biochemistry, 41, 8221-8228.  
11327865 D.Neidhart, Y.Wei, C.Cassidy, J.Lin, W.W.Cleland, and P.A.Frey (2001).
Correlation of low-barrier hydrogen bonding and oxyanion binding in transition state analogue complexes of chymotrypsin.
  Biochemistry, 40, 2439-2447.
PDB codes: 1gg6 1ggd
11358514 P.A.Wright, R.C.Wilmouth, I.J.Clifton, and C.J.Schofield (2001).
Kinetic and crystallographic analysis of complexes formed between elastase and peptides from beta-casein.
  Eur J Biochem, 268, 2969-2974.
PDB code: 1h9l
10713514 A.Mac Sweeney, G.Birrane, M.A.Walsh, T.O'Connell, J.P.Malthouse, and T.M.Higgins (2000).
Crystal structure of delta-chymotrypsin bound to a peptidyl chloromethyl ketone inhibitor.
  Acta Crystallogr D Biol Crystallogr, 56, 280-286.
PDB code: 1dlk
10677236 F.Narjes, M.Brunetti, S.Colarusso, B.Gerlach, U.Koch, G.Biasiol, D.Fattori, R.De Francesco, V.G.Matassa, and C.Steinkühler (2000).
Alpha-ketoacids are potent slow binding inhibitors of the hepatitis C virus NS3 protease.
  Biochemistry, 39, 1849-1861.  
10813840 M.Shokhen, and A.Albeck (2000).
Factors determining the relative stability of anionic tetrahedral complexes in serine protease catalysis and inhibition.
  Proteins, 40, 154-167.  
10944388 V.Z.Pletnev, T.S.Zamolodchikova, W.A.Pangborn, and W.L.Duax (2000).
Crystal structure of bovine duodenase, a serine protease, with dual trypsin and chymotrypsin-like specificities.
  Proteins, 41, 8.
PDB code: 1euf
10102985 H.Czapinska, and J.Otlewski (1999).
Structural and energetic determinants of the S1-site specificity in serine proteases.
  Eur J Biochem, 260, 571-595.  
10320365 J.W.Simons, R.C.Cox, M.R.Egmond, and H.M.Verheij (1999).
Rational design of alpha-keto triglyceride analogues as inhibitors for Staphylococcus hyicus lipase.
  Biochemistry, 38, 6346-6351.  
9914536 P.Hudáky, G.Kaslik, I.Venekei, and L.Gráf (1999).
The differential specificity of chymotrypsin A and B is determined by amino acid 226.
  Eur J Biochem, 259, 528-533.  
10481006 S.Yoshizawa, D.Fourmy, and J.D.Puglisi (1999).
Recognition of the codon-anticodon helix by ribosomal RNA.
  Science, 285, 1722-1725.  
10328262 T.K.Harris, and A.S.Mildvan (1999).
High-precision measurement of hydrogen bond lengths in proteins by nuclear magnetic resonance methods.
  Proteins, 35, 275-282.  
  9680068 A.Amour, M.Reboud-Ravaux, E.de Rosny, A.Abouabdellah, J.P.Bégue, D.Bonnet-Delpon, and M.Le Gall (1998).
Stereoselective synthesis of peptidyl trifluoromethyl alcohols and ketones: inhibitory potency against human leucocyte elastase, cathepsin G, porcine pancreatic elastase and HIV-1 protease.
  J Pharm Pharmacol, 50, 593-600.  
9718318 J.Lin, C.S.Cassidy, and P.A.Frey (1998).
Correlations of the basicity of His 57 with transition state analogue binding, substrate reactivity, and the strength of the low-barrier hydrogen bond in chymotrypsin.
  Biochemistry, 37, 11940-11948.  
9843946 J.Lin, W.M.Westler, W.W.Cleland, J.L.Markley, and P.A.Frey (1998).
Fractionation factors and activation energies for exchange of the low barrier hydrogen bonding proton in peptidyl trifluoromethyl ketone complexes of chymotrypsin.
  Proc Natl Acad Sci U S A, 95, 14664-14668.  
9578548 M.P.Weir, S.S.Bethell, A.Cleasby, C.J.Campbell, R.J.Dennis, C.J.Dix, H.Finch, H.Jhoti, C.J.Mooney, S.Patel, C.M.Tang, M.Ward, A.J.Wonacott, and C.W.Wharton (1998).
Novel natural product 5,5-trans-lactone inhibitors of human alpha-thrombin: mechanism of action and structural studies.
  Biochemistry, 37, 6645-6657.
PDB codes: 1awf 1awh
9748211 W.W.Cleland, P.A.Frey, and J.A.Gerlt (1998).
The low barrier hydrogen bond in enzymatic catalysis.
  J Biol Chem, 273, 25529-25532.  
9348662 C.L.Perrin, and J.B.Nielson (1997).
"Strong" hydrogen bonds in chemistry and biology.
  Annu Rev Phys Chem, 48, 511-544.  
9109667 C.S.Cassidy, J.Lin, and P.A.Frey (1997).
A new concept for the mechanism of action of chymotrypsin: the role of the low-barrier hydrogen bond.
  Biochemistry, 36, 4576-4584.  
9195866 J.A.Gerlt, M.M.Kreevoy, W.Cleland, and P.A.Frey (1997).
Understanding enzymic catalysis: the importance of short, strong hydrogen bonds.
  Chem Biol, 4, 259-267.  
8961961 C.J.Halkides, Y.Q.Wu, and C.J.Murray (1996).
A low-barrier hydrogen bond in subtilisin: 1H and 15N NMR studies with peptidyl trifluoromethyl ketones.
  Biochemistry, 35, 15941-15948.  
  8142889 C.W.Sokolik, T.C.Liang, and F.Wold (1994).
Studies on the specificity of acetylaminoacyl-peptide hydrolase.
  Protein Sci, 3, 126-131.  
8189835 P.D.Edwards, and P.R.Bernstein (1994).
Synthetic inhibitors of elastase.
  Med Res Rev, 14, 127-194.  
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 codes are shown on the right.