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

 

 

 

 

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Contents
Protein chain
316 a.a. *
Ligands
0ZN
Metals
_ZN
_CA ×4
Waters ×144
* Residue conservation analysis
PDB id:
1tmn
Name: Hydrolase/hydrolase inhibitor
Title: Binding of n-carboxymethyl dipeptide inhibitors to thermolysin determined by x-ray crystallography. A novel class of transition- state analogues for zinc peptidases
Structure: Thermolysin. Chain: e. Engineered: yes
Source: Bacillus thermoproteolyticus. Organism_taxid: 1427. Gene: npr
Biol. unit: Tetramer (from PQS)
Resolution:
1.90Å     R-factor:   0.171    
Authors: A.F.Monzingo,B.W.Matthews
Key ref:
A.F.Monzingo and B.W.Matthews (1984). Binding of N-carboxymethyl dipeptide inhibitors to thermolysin determined by X-ray crystallography: a novel class of transition-state analogues for zinc peptidases. Biochemistry, 23, 5724-5729. PubMed id: 6395881 DOI: 10.1021/bi00319a010
Date:
29-Jun-87     Release date:   09-Jan-89    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00800  (THER_BACTH) -  Thermolysin from Bacillus thermoproteolyticus
Seq:
Struc: 		 
Seq:
Struc: 		548 a.a.
316 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.3.4.24.27  - thermolysin.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Preferential cleavage: Xaa-|-Leu > Xaa-|-Phe.
      Cofactor: Ca(2+); Zn(2+)

 

 
DOI no: 10.1021/bi00319a010 Biochemistry 23:5724-5729 (1984)
PubMed id: 6395881  
 
 
Binding of N-carboxymethyl dipeptide inhibitors to thermolysin determined by X-ray crystallography: a novel class of transition-state analogues for zinc peptidases.
A.F.Monzingo, B.W.Matthews.
 
  ABSTRACT  
 
The mode of binding of the specific thermolysin inhibitor N-(1-carboxy-3-phenylpropyl)-L-leucyl-L-tryptophan (KI approximately 5 X 10(-8) M) [Maycock, A. L., DeSousa, D. M., Payne, L. G., ten Broeke, J., Wu, M. T., & Patchett, A. A. (1981) Biochem. Biophys. Res. Commun. 102, 963-969] has been determined by X-ray crystallography and refined to an R value of 17.1% at 1.9-A resolution. The inhibitor binds to thermolysin with both oxygens of the N-carboxymethyl group liganded to the zinc to give overall pentacoordination of the metal. The bidentate ligation of the inhibitor differs from the monodentate binding seen previously for carboxylate-zinc interactions in thermolysin and is closer to the bidentate geometry observed for the binding of hydroxamates [Holmes, M. A., & Matthews, B. W. (1981) Biochemistry 20, 6912-6920]. The geometry of the inhibitor and its interactions with the protein have a number of elements in common with the presumed transition state formed during peptide hydrolysis. The observed zinc ligation supports the previous suggestion that a pentacoordinate intermediate participates in the mechanism of catalysis. However, the alpha-amino nitrogen of the inhibitor is close to Glu-143, suggesting that this residue might accept a proton from an attacking water molecule (as proposed before) and subsequently donate this proton to the leaving nitrogen. By analogy with thermolysin, it is proposed that a related mechanism should be considered for peptide cleavage by carboxypeptidase A.(ABSTRACT TRUNCATED AT 250 WORDS)
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20544098 M.Qaiser Fatmi, T.S.Hofer, and B.M.Rode (2010).
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The thermolysin family (m4) of enzymes: therapeutic and biotechnological potential.
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19003991 X.Wang, M.Kirberger, F.Qiu, G.Chen, and J.J.Yang (2009).
Towards predicting Ca2+-binding sites with different coordination numbers in proteins with atomic resolution.
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17516427 E.Proschak, M.Rupp, S.Derksen, and G.Schneider (2008).
Shapelets: possibilities and limitations of shape-based virtual screening.
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16617426 H.Deng, G.Chen, W.Yang, and J.J.Yang (2006).
Predicting calcium-binding sites in proteins - a graph theory and geometry approach.
  Proteins, 64, 34-42.  
16167086 A.M.Kennedy, M.Inada, S.M.Krane, P.T.Christie, B.Harding, C.López-Otín, L.M.Sánchez, A.A.Pannett, A.Dearlove, C.Hartley, M.H.Byrne, A.A.Reed, M.A.Nesbit, M.P.Whyte, and R.V.Thakker (2005).
MMP13 mutation causes spondyloepimetaphyseal dysplasia, Missouri type (SEMD(MO).
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16008342 J.W.Arndt, W.Yu, F.Bi, and R.C.Stevens (2005).
Crystal structure of botulinum neurotoxin type G light chain: serotype divergence in substrate recognition.
  Biochemistry, 44, 9574-9580.
PDB code: 1zb7
15027050 S.Swaminathan, S.Eswaramoorthy, and D.Kumaran (2004).
Structure and enzymatic activity of botulinum neurotoxins.
  Mov Disord, 19, S17-S22.  
12325160 E.Bianchi, and A.Pessi (2002).
Inhibiting viral proteases: challenges and opportunities.
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11839307 J.W.Arndt, B.Hao, V.Ramakrishnan, T.Cheng, S.I.Chan, and M.K.Chan (2002).
Crystal structure of a novel carboxypeptidase from the hyperthermophilic archaeon Pyrococcus furiosus.
  Structure, 10, 215-224.
PDB codes: 1k9x 1ka2 1ka4
11969409 P.Ingallinella, D.Fattori, S.Altamura, C.Steinkühler, U.Koch, D.Cicero, R.Bazzo, R.Cortese, E.Bianchi, and A.Pessi (2002).
Prime site binding inhibitors of a serine protease: NS3/4A of hepatitis C virus.
  Biochemistry, 41, 5483-5492.  
12395431 V.Kairys, and M.K.Gilson (2002).
Enhanced docking with the mining minima optimizer: acceleration and side-chain flexibility.
  J Comput Chem, 23, 1656-1670.  
10651278 A.C.English, S.H.Done, L.S.Caves, C.R.Groom, and R.E.Hubbard (1999).
Locating interaction sites on proteins: the crystal structure of thermolysin soaked in 2% to 100% isopropanol.
  Proteins, 37, 628-640.
PDB codes: 1tli 1tlx 2tli 2tlx 3tli 4tli 5tli 6tli 7tli 8tli
10387075 K.Fukasawa, K.M.Fukasawa, H.Iwamoto, J.Hirose, and M.Harada (1999).
The HELLGH motif of rat liver dipeptidyl peptidase III is involved in zinc coordination and the catalytic activity of the enzyme.
  Biochemistry, 38, 8299-8303.  
10545376 U.Ryde (1999).
Carboxylate binding modes in zinc proteins: A theoretical study
  Biophys J, 77, 2777-2787.  
10387007 W.T.Lowther, A.M.Orville, D.T.Madden, S.Lim, D.H.Rich, and B.W.Matthews (1999).
Escherichia coli methionine aminopeptidase: implications of crystallographic analyses of the native, mutant, and inhibited enzymes for the mechanism of catalysis.
  Biochemistry, 38, 7678-7688.
PDB codes: 2mat 3mat 4mat
10555963 W.T.Lowther, Y.Zhang, P.B.Sampson, J.F.Honek, and B.W.Matthews (1999).
Insights into the mechanism of Escherichia coli methionine aminopeptidase from the structural analysis of reaction products and phosphorus-based transition-state analogues.
  Biochemistry, 38, 14810-14819.
PDB codes: 1c21 1c22 1c23 1c24 1c27
9753696 A.Banbula, J.Potempa, J.Travis, C.Fernandez-Catalán, K.Mann, R.Huber, W.Bode, and F.Medrano (1998).
Amino-acid sequence and three-dimensional structure of the Staphylococcus aureus metalloproteinase at 1.72 A resolution.
  Structure, 6, 1185-1193.
PDB code: 1bqb
9720222 S.Kojima, T.Kumazaki, S.Ishii, and K.Miura (1998).
Primary structure of Streptomyces griseus metalloendopeptidase II.
  Biosci Biotechnol Biochem, 62, 1392-1398.  
9245420 S.T.Huang, W.E.Choi, C.Bloom, M.Leuenberger, and M.F.Dunn (1997).
Carboxylate ions are strong allosteric ligands for the HisB10 sites of the R-state insulin hexamer.
  Biochemistry, 36, 9878-9888.  
9262642 U.Eichhorn, A.S.Bommarius, K.Drauz, and H.D.Jakubke (1997).
Synthesis of dipeptides by suspension-to-suspension conversion via thermolysin catalysis: from analytical to preparative scale.
  J Pept Sci, 3, 245-251.  
8615890 A.J.Turner, and L.J.Murphy (1996).
Molecular pharmacology of endothelin converting enzymes.
  Biochem Pharmacol, 51, 91.  
7622493 A.Beaumont, M.J.O'Donohue, N.Paredes, N.Rousselet, M.Assicot, C.Bohuon, M.C.Fournié-Zaluski, and B.P.Roques (1995).
The role of histidine 231 in thermolysin-like enzymes. A site-directed mutagenesis study.
  J Biol Chem, 270, 16803-16808.  
7561976 C.McMartin, and R.S.Bohacek (1995).
Flexible matching of test ligands to a 3D pharmacophore using a molecular superposition force field: comparison of predicted and experimental conformations of inhibitors of three enzymes.
  J Comput Aided Mol Des, 9, 237-250.  
8789192 C.S.Poornima, and P.M.Dean (1995).
Hydration in drug design. 1. Multiple hydrogen-bonding features of water molecules in mediating protein-ligand interactions.
  J Comput Aided Mol Des, 9, 500-512.  
7738608 G.Klebe, T.Mietzner, and F.Weber (1994).
Different approaches toward an automatic structural alignment of drug molecules: applications to sterol mimics, thrombin and thermolysin inhibitors.
  J Comput Aided Mol Des, 8, 751-778.  
7876902 G.Klebe, and T.Mietzner (1994).
A fast and efficient method to generate biologically relevant conformations.
  J Comput Aided Mol Des, 8, 583-606.  
8090713 J.C.Spurlino, A.M.Smallwood, D.D.Carlton, T.M.Banks, K.J.Vavra, J.S.Johnson, E.R.Cook, J.Falvo, R.C.Wahl, and T.A.Pulvino (1994).
1.56 A structure of mature truncated human fibroblast collagenase.
  Proteins, 19, 98.
PDB code: 1hfc
  7529108 L.J.Murphy, R.Corder, A.I.Mallet, and A.J.Turner (1994).
Generation by the phosphoramidon-sensitive peptidases, endopeptidase-24.11 and thermolysin, of endothelin-1 and c-terminal fragment from big endothelin-1.
  Br J Pharmacol, 113, 137-142.  
7964924 R.L.DesJarlais, and J.S.Dixon (1994).
A shape- and chemistry-based docking method and its use in the design of HIV-1 protease inhibitors.
  J Comput Aided Mol Des, 8, 231-242.  
8212315 M.A.Navia, and D.A.Peattie (1993).
Structure-based drug design: applications in immunopharmacology and immunosuppression.
  Trends Pharmacol Sci, 14, 189-195.  
  8392606 M.Hijikata, H.Mizushima, T.Akagi, S.Mori, N.Kakiuchi, N.Kato, T.Tanaka, K.Kimura, and K.Shimotohno (1993).
Two distinct proteinase activities required for the processing of a putative nonstructural precursor protein of hepatitis C virus.
  J Virol, 67, 4665-4675.  
  1304887 E.Meyer (1992).
Internal water molecules and H-bonding in biological macromolecules: a review of structural features with functional implications.
  Protein Sci, 1, 1543-1562.  
1633859 R.C.Garratt, and H.Jhotí (1992).
A molecular model for the tumour-associated antigen, p97, suggests a Zn-binding function.
  FEBS Lett, 305, 55-61.  
1633827 W.Stark, R.A.Pauptit, K.S.Wilson, and J.N.Jansonius (1992).
The structure of neutral protease from Bacillus cereus at 0.2-nm resolution.
  Eur J Biochem, 207, 781-791.
PDB code: 1npc
  2548550 M.R.Attwood (1989).
Chemical design of cilazapril.
  Br J Clin Pharmacol, 27, 133S-137S.  
3709536 D.E.Tronrud, A.F.Monzingo, and B.W.Matthews (1986).
Crystallographic structural analysis of phosphoramidates as inhibitors and transition-state analogs of thermolysin.
  Eur J Biochem, 157, 261-268.
PDB codes: 1tlp 2tmn
3463986 D.W.Christianson, and W.N.Lipscomb (1986).
X-ray crystallographic investigation of substrate binding to carboxypeptidase A at subzero temperature.
  Proc Natl Acad Sci U S A, 83, 7568-7572.
PDB code: 3cpa
2988395 D.G.Hangauer, P.Gund, J.D.Andose, B.L.Bush, E.M.Fluder, E.F.McIntyre, and G.M.Smith (1985).
Modeling the mechanism of peptide cleavage by thermolysin.
  Ann N Y Acad Sci, 439, 124-139.  
3863130 D.W.Christianson, and W.N.Lipscomb (1985).
Binding of a possible transition state analogue to the active site of carboxypeptidase A.
  Proc Natl Acad Sci U S A, 82, 6840-6844.  
2999531 M.J.Wyvratt, and A.A.Patchett (1985).
Recent developments in the design of angiotensin-converting enzyme inhibitors.
  Med Res Rev, 5, 483-531.  
3840231 S.J.Gardell, C.S.Craik, D.Hilvert, M.S.Urdea, and W.J.Rutter (1985).
Site-directed mutagenesis shows that tyrosine 248 of carboxypeptidase A does not play a crucial role in catalysis.
  Nature, 317, 551-555.  
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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