PDBsum entry 1qf2

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Hydrolase PDB id
Jmol PyMol
Protein chain
316 a.a. *
DMS ×3
_CA ×4
Waters ×237
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Thermolysin (E.C. complexed with (2-sulphanyl-3- phenylpropanoyl)-gly-(5-phenylproline). Parameters for zn- monodentation of mercaptoacyldipeptides in metalloendopeptidase
Structure: Protein (thermolysin). Chain: a. Ec:
Source: Bacillus thermoproteolyticus. Organism_taxid: 1427
Biol. unit: Dimer (from PQS)
2.06Å     R-factor:   0.159     R-free:   0.222
Authors: J.-F.Gaucher,M.Selkti,G.Tiraboschi,T.Prange,B.P.Roques, A.Tomas,M.C.Fournie-Zaluski
Key ref:
J.F.Gaucher et al. (1999). Crystal structures of alpha-mercaptoacyldipeptides in the thermolysin active site: structural parameters for a Zn monodentation or bidentation in metalloendopeptidases. Biochemistry, 38, 12569-12576. PubMed id: 10504225 DOI: 10.1021/bi991043z
06-Apr-99     Release date:   29-Dec-99    
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/bi991043z Biochemistry 38:12569-12576 (1999)
PubMed id: 10504225  
Crystal structures of alpha-mercaptoacyldipeptides in the thermolysin active site: structural parameters for a Zn monodentation or bidentation in metalloendopeptidases.
J.F.Gaucher, M.Selkti, G.Tiraboschi, T.Prangé, B.P.Roques, A.Tomas, M.C.Fournié-Zaluski.
Three alpha-mercaptoacyldipeptides differing essentially in the size of their C-terminal residues have been crystallized in the thermolysin active site. A new mode of binding was observed for 3 [HS-CH(CH(2)Ph)CO-Phe-Tyr] and 4 [HS-CH((CH(2))(4)CH(3))CO-Phe-Ala], in which the mercaptoacyl moieties act as bidentates with Zn-S and Zn-O distances of 2.3 and 2.4 A, respectively, the side chains fitting the S(1), S(1)', and S(2)' pockets. Moreover, a distance of 3.1 A between the sulfur atom and the OE1 of Glu(143) suggests that they are H-bonded and that one of these atoms is protonated. This H-bond network involving Glu(143), the mercaptoacyl group of the inhibitor, and the Zn ion could be considered a "modified" transition state mimic of the peptide bond hydrolysis. Due to the presence of the hindering (5-phenyl)proline, the inhibitor HS-CH(CH(2)Ph)CO-Gly-(5-Ph)Pro (2) interacts through the usual Zn monodentation via the thiol group and occupancy of S(1)' and S(2)' subsites by the aromatic moieties, the proline ring being outside the active site. The inhibitory potencies are consistent with these structural data, with higher affinities for 3 (4.2 x 10(-)(8) M) and 4 (4.8 x 10(-)(8) M) than for 2 (1.2 x 10(-)(6) M). The extension of the results, obtained with thermolysin being considered as the model of physiological zinc metallopeptidases, allows inhibitor-recognition modes for other peptidases, such as angiotensin converting enzyme and neutral endopeptidase, to be proposed and opens interesting possibilities for the design of new classes of inhibitors.

Literature references that cite this PDB file's key reference

  PubMed id Reference
20640477 S.Kostenko, M.T.Khan, I.Sylte, and U.Moens (2011).
The diterpenoid alkaloid noroxoaconitine is a Mapkap kinase 5 (MK5/PRAK) inhibitor.
  Cell Mol Life Sci, 68, 289-301.  
19685535 L.Hocharoen, and J.A.Cowan (2009).
Metallotherapeutics: novel strategies in drug design.
  Chemistry, 15, 8670-8676.  
19152630 O.A.Adekoya, and I.Sylte (2009).
The thermolysin family (m4) of enzymes: therapeutic and biotechnological potential.
  Chem Biol Drug Des, 73, 7.  
19724785 Y.Z.Zhang, S.F.Zhu, Y.Cai, H.X.Mao, and Q.L.Zhou (2009).
Copper-catalyzed enantioselective carbenoid insertion into S-H bonds.
  Chem Commun (Camb), (), 5362-5364.  
18041759 B.Seebeck, I.Reulecke, A.Kämper, and M.Rarey (2008).
Modeling of metal interaction geometries for protein-ligand docking.
  Proteins, 71, 1237-1254.  
18074211 G.Lutfullah, F.Amin, Z.Khan, N.Azhar, M.K.Azim, S.Noor, and K.Shoukat (2008).
Homology modeling of hemagglutinin/protease [HA/P (vibriolysin)] from Vibrio cholerae: sequence comparision, residue interactions and molecular mechanism.
  Protein J, 27, 105-114.  
17704566 C.Oefner, S.Pierau, H.Schulz, and G.E.Dale (2007).
Structural studies of a bifunctional inhibitor of neprilysin and DPP-IV.
  Acta Crystallogr D Biol Crystallogr, 63, 975-981.
PDB code: 2qpj
17618468 N.H.Gokhale, S.Bradford, and J.A.Cowan (2007).
Stimulation and oxidative catalytic inactivation of thermolysin by copper.Cys-Gly-His-Lys.
  J Biol Inorg Chem, 12, 981-987.  
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
12832763 M.Selkti, A.Tomas, J.F.Gaucher, T.Prangé, M.C.Fournié-Zaluski, H.Chen, and B.P.Roques (2003).
Interactions of a new alpha-aminophosphinic derivative inside the active site of TLN (thermolysin): a model for zinc-metalloendopeptidase inhibition.
  Acta Crystallogr D Biol Crystallogr, 59, 1200-1205.
PDB code: 1os0
11859085 Kreij, B.van den Burg, G.Venema, G.Vriend, V.G.Eijsink, and J.E.Nielsen (2002).
The effects of modifying the surface charge on the catalytic activity of a thermolysin-like protease.
  J Biol Chem, 277, 15432-15438.  
12210153 J.Antony, N.Gresh, L.Olsen, L.Hemmingsen, C.J.Schofield, and R.Bauer (2002).
Binding of D- and L-captopril inhibitors to metallo-beta-lactamase studied by polarizable molecular mechanics and quantum mechanics.
  J Comput Chem, 23, 1281-1296.  
12454500 J.F.Gaucher, M.Selkti, T.Prangé, and A.Tomas (2002).
The 2.2 A resolution structure of thermolysin (TLN) crystallized in the presence of potassium thiocyanate.
  Acta Crystallogr D Biol Crystallogr, 58, 2198-2200.
PDB code: 1gxw
11790786 M.M.Bernardo, S.Brown, Z.H.Li, R.Fridman, and S.Mobashery (2002).
Design, synthesis, and characterization of potent, slow-binding inhibitors that are selective for gelatinases.
  J Biol Chem, 277, 11201-11207.  
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.