PDBsum entry 4tln

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Hydrolase (metalloproteinase) PDB id
Protein chain
316 a.a. *
_CA ×4
Waters ×150
* Residue conservation analysis
PDB id:
Name: Hydrolase (metalloproteinase)
Title: Binding of hydroxamic acid inhibitors to crystalline thermol suggests a pentacoordinate zinc intermediate in catalysis
Structure: Thermolysin. Chain: a. Engineered: yes
Source: Bacillus thermoproteolyticus. Organism_taxid: 1427
2.30Å     R-factor:   0.169    
Authors: B.W.Matthews,M.A.Holmes
Key ref:
M.A.Holmes and B.W.Matthews (1981). Binding of hydroxamic acid inhibitors to crystalline thermolysin suggests a pentacoordinate zinc intermediate in catalysis. Biochemistry, 20, 6912-6920. PubMed id: 7317361 DOI: 10.1021/bi00527a026
08-Feb-82     Release date:   26-May-82    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P00800  (THER_BACTH) -  Thermolysin
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.  - Thermolysin.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Preferential cleavage: Xaa-|-Leu > Xaa-|-Phe.
      Cofactor: Ca(2+); Zn(2+)
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     proteolysis   1 term 
  Biochemical function     metalloendopeptidase activity     1 term  


DOI no: 10.1021/bi00527a026 Biochemistry 20:6912-6920 (1981)
PubMed id: 7317361  
Binding of hydroxamic acid inhibitors to crystalline thermolysin suggests a pentacoordinate zinc intermediate in catalysis.
M.A.Holmes, B.W.Matthews.
No abstract given.


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).
The stability of [Zn(NH(3))(4)](2+) in water: A quantum mechanical/molecular mechanical molecular dynamics study.
  Phys Chem Chem Phys, 12, 9713-9718.  
19585464 G.A.Dalkas, A.Papakyriakou, A.Vlamis-Gardikas, and G.A.Spyroulias (2009).
Insights into the anthrax lethal factor-substrate interaction and selectivity using docking and molecular dynamics simulations.
  Protein Sci, 18, 1774-1785.  
19152630 O.A.Adekoya, and I.Sylte (2009).
The thermolysin family (m4) of enzymes: therapeutic and biotechnological potential.
  Chem Biol Drug Des, 73, 7.  
18041759 B.Seebeck, I.Reulecke, A.Kämper, and M.Rarey (2008).
Modeling of metal interaction geometries for protein-ligand docking.
  Proteins, 71, 1237-1254.  
17516427 E.Proschak, M.Rupp, S.Derksen, and G.Schneider (2008).
Shapelets: possibilities and limitations of shape-based virtual screening.
  J Comput Chem, 29, 108-114.  
18451556 H.Kobayashi, N.Morisaki, H.Miyachi, and Y.Hashimoto (2008).
Coordination of divalent metal cation to amide group to form adduct ion in FAB mass spectrometry: implication of Zn2+ in enzymatic hydrolysis of amide bond.
  Chem Pharm Bull (Tokyo), 56, 672-676.  
16800620 H.A.Gennadios, D.A.Whittington, X.Li, C.A.Fierke, and D.W.Christianson (2006).
Mechanistic inferences from the binding of ligands to LpxC, a metal-dependent deacetylase.
  Biochemistry, 45, 7940-7948.
PDB codes: 2go3 2go4
16885166 K.Ito, Y.Nakajima, Y.Onohara, M.Takeo, K.Nakashima, F.Matsubara, T.Ito, and T.Yoshimoto (2006).
Crystal structure of aminopeptidase N (proteobacteria alanyl aminopeptidase) from Escherichia coli and conformational change of methionine 260 involved in substrate recognition.
  J Biol Chem, 281, 33664-33676.
PDB codes: 2dq6 2dqm
16342948 A.L.McClerren, S.Endsley, J.L.Bowman, N.H.Andersen, Z.Guan, J.Rudolph, and C.R.Raetz (2005).
A slow, tight-binding inhibitor of the zinc-dependent deacetylase LpxC of lipid A biosynthesis with antibiotic activity comparable to ciprofloxacin.
  Biochemistry, 44, 16574-16583.  
15526325 M.Kontoyianni, G.S.Sokol, and L.M.McClellan (2005).
Evaluation of library ranking efficacy in virtual screening.
  J Comput Chem, 26, 11-22.  
14718924 B.E.Turk, T.Y.Wong, R.Schwarzenbacher, E.T.Jarrell, S.H.Leppla, R.J.Collier, R.C.Liddington, and L.C.Cantley (2004).
The structural basis for substrate and inhibitor selectivity of the anthrax lethal factor.
  Nat Struct Mol Biol, 11, 60-66.
PDB codes: 1pwq 1pwu 1pwv 1pww
12786398 Y.Wu, X.Yuan, X.Gao, H.Fang, and J.Zi (2003).
Universal behavior of localization of residue fluctuations in globular proteins.
  Phys Rev E Stat Nonlin Soft Matter Phys, 67, 041909.  
12235156 F.Guo, L.Esser, S.K.Singh, M.R.Maurizi, and D.Xia (2002).
Crystal structure of the heterodimeric complex of the adaptor, ClpS, with the N-domain of the AAA+ chaperone, ClpA.
  J Biol Chem, 277, 46753-46762.
PDB codes: 1mbu 1mbv 1mbx
12437105 J.A.Krauser, J.Potempa, J.Travis, and J.C.Powers (2002).
Inhibition of arginine gingipains (RgpB and HRgpA) with benzamidine inhibitors: zinc increases inhibitory potency.
  Biol Chem, 383, 1193-1198.  
12019092 J.M.Clements, F.Coignard, I.Johnson, S.Chandler, S.Palan, A.Waller, J.Wijkmans, and M.G.Hunter (2002).
Antibacterial activities and characterization of novel inhibitors of LpxC.
  Antimicrob Agents Chemother, 46, 1793-1799.  
11148046 J.E.Jackman, C.R.Raetz, and C.A.Fierke (2001).
Site-directed mutagenesis of the bacterial metalloamidase UDP-(3-O-acyl)-N-acetylglucosamine deacetylase (LpxC). Identification of the zinc binding site.
  Biochemistry, 40, 514-523.  
11158755 J.M.Clements, R.P.Beckett, A.Brown, G.Catlin, M.Lobell, S.Palan, W.Thomas, M.Whittaker, S.Wood, S.Salama, P.J.Baker, H.F.Rodgers, V.Barynin, D.W.Rice, and M.G.Hunter (2001).
Antibiotic activity and characterization of BB-3497, a novel peptide deformylase inhibitor.
  Antimicrob Agents Chemother, 45, 563-570.
PDB codes: 1g27 1g2a
10649451 I.Herrera-Camacho, R.Morales-Monterrosas, and R.Quiróz-Alvarez (2000).
Aminopeptidase yscCo-II: a new cobalt-dependent aminopeptidase from yeast-purification and biochemical characterization.
  Yeast, 16, 219-229.  
10753902 J.E.Jackman, C.A.Fierke, L.N.Tumey, M.Pirrung, T.Uchiyama, S.H.Tahir, O.Hindsgaul, and C.R.Raetz (2000).
Antibacterial agents that target lipid A biosynthesis in gram-negative bacteria. Inhibition of diverse UDP-3-O-(r-3-hydroxymyristoyl)-n-acetylglucosamine deacetylases by substrate analogs containing zinc binding motifs.
  J Biol Chem, 275, 11002-11009.  
11076537 W.L.Mock, and H.Cheng (2000).
Principles of hydroxamate inhibition of metalloproteases: carboxypeptidase A.
  Biochemistry, 39, 13945-13952.  
  9729602 M.B.Rao, A.M.Tanksale, M.S.Ghatge, and V.V.Deshpande (1998).
Molecular and biotechnological aspects of microbial proteases.
  Microbiol Mol Biol Rev, 62, 597-635.  
9125517 W.L.Mock, and J.Yao (1997).
Kinetic characterization of the serralysins: a divergent catalytic mechanism pertaining to astacin-type metalloproteases.
  Biochemistry, 36, 4949-4958.  
8647077 B.Chevrier, H.D'Orchymont, C.Schalk, C.Tarnus, and D.Moras (1996).
The structure of the Aeromonas proteolytica aminopeptidase complexed with a hydroxamate inhibitor. Involvement in catalysis of Glu151 and two zinc ions of the co-catalytic unit.
  Eur J Biochem, 237, 393-398.
PDB code: 1igb
8879550 C.Tarnus, J.M.Rémy, and H.d'Orchymont (1996).
3-Amino-2-hydroxy-propionaldehyde and 3-amino-1-hydroxy-propan-2-one derivatives: new classes of aminopeptidase inhibitors.
  Bioorg Med Chem, 4, 1287-1297.  
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.  
7737183 F.Grams, P.Reinemer, J.C.Powers, T.Kleine, M.Pieper, H.Tschesche, R.Huber, and W.Bode (1995).
X-ray structures of human neutrophil collagenase complexed with peptide hydroxamate and peptide thiol inhibitors. Implications for substrate binding and rational drug design.
  Eur J Biochem, 228, 830-841.
PDB codes: 1jao 1jaq
8564408 J.H.Hogg, I.R.Ollmann, J.Z.Haeggström, A.Wetterholm, B.Samuelsson, and C.H.Wong (1995).
Amino hydroxamic acids as potent inhibitors of leukotriene A4 hydrolase.
  Bioorg Med Chem, 3, 1405-1415.  
8168535 H.Le Moual, N.Dion, B.P.Roques, P.Crine, and G.Boileau (1994).
Asp650 is crucial for catalytic activity of neutral endopeptidase 24-11.
  Eur J Biochem, 221, 475-480.  
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
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.  
7972000 S.D.Malley, J.M.Grange, F.Hamedi-Sangsari, and J.R.Vila (1994).
Synergistic anti-human immunodeficiency virus type 1 effect of hydroxamate compounds with 2',3'-dideoxyinosine in infected resting human lymphocytes.
  Proc Natl Acad Sci U S A, 91, 11017-11021.  
  8137810 W.Bode, P.Reinemer, R.Huber, T.Kleine, S.Schnierer, and H.Tschesche (1994).
The X-ray crystal structure of the catalytic domain of human neutrophil collagenase inhibited by a substrate analogue reveals the essentials for catalysis and specificity.
  EMBO J, 13, 1263-1269.
PDB code: 1jap
1576995 H.Nar, R.Huber, A.Messerschmidt, A.C.Filippou, M.Barth, M.Jaquinod, M.van de Kamp, and G.W.Canters (1992).
Characterization and crystal structure of zinc azurin, a by-product of heterologous expression in Escherichia coli of Pseudomonas aeruginosa copper azurin.
  Eur J Biochem, 205, 1123-1129.
PDB code: 1e67
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
1672519 A.Helene, A.Beaumont, and B.P.Roques (1991).
Functional residues at the active site of aminopeptidase N.
  Eur J Biochem, 196, 385-393.  
  1710977 A.Volbeda, A.Lahm, F.Sakiyama, and D.Suck (1991).
Crystal structure of Penicillium citrinum P1 nuclease at 2.8 A resolution.
  EMBO J, 10, 1607-1618.  
1818094 G.Bolis, L.Di Pace, and F.Fabrocini (1991).
A machine learning approach to computer-aided molecular design.
  J Comput Aided Mol Des, 5, 617-628.  
2715793 C.Giessner-Prettre, and O.Jacob (1989).
A theoretical study of Zn++ interacting with models of ligands present at the thermolysin active site.
  J Comput Aided Mol Des, 3, 23-37.  
3151020 A.E.Eriksson, P.M.Kylsten, T.A.Jones, and A.Liljas (1988).
Crystallographic studies of inhibitor binding sites in human carbonic anhydrase II: a pentacoordinated binding of the SCN- ion to the zinc at high pH.
  Proteins, 4, 283-293.
PDB codes: 2ca2 3ca2
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
3514216 J.W.Fox, R.Campbell, L.Beggerly, and J.B.Bjarnason (1986).
Substrate specificities and inhibition of two hemorrhagic zinc proteases Ht-c and Ht-d from Crotalus atrox venom.
  Eur J Biochem, 156, 65-72.  
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.  
  3905371 H.Weinstein, J.Rabinowitz, M.N.Liebman, and R.Osman (1985).
Determinants of molecular reactivity as criteria for predicting toxicity: problems and approaches.
  Environ Health Perspect, 61, 147-162.  
6321177 M.C.Fournie-Zaluski, E.Lucas, G.Waksman, and B.P.Roques (1984).
Differences in the structural requirements for selective interaction with neutral metalloendopeptidase (enkephalinase) or angiotensin-converting enzyme. Molecular investigation by use of new thiol inhibitors.
  Eur J Biochem, 139, 267-274.  
6361807 G.R.Stark, and P.A.Bartlett (1983).
Design and use of potent, specific enzyme inhibitors.
  Pharmacol Ther, 23, 45-78.  
6574483 S.I.Wayne, and J.S.Fruton (1983).
Thermolysin-catalyzed peptide bond synthesis.
  Proc Natl Acad Sci U S A, 80, 3241-3244.  
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.