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PDBsum entry 3f28

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protein ligands metals links
Hydrolase PDB id
3f28
Jmol
Contents
Protein chain
316 a.a. *
Ligands
S7B
Metals
_CA ×4
_ZN
Waters ×137
* Residue conservation analysis
PDB id:
3f28
Name: Hydrolase
Title: Thermolysin inhibition
Structure: Thermolysin. Chain: a. Fragment: unp residues 233-548. Synonym: thermostable neutral proteinase. Ec: 3.4.24.27
Source: Bacillus thermoproteolyticus. Organism_taxid: 1427
Resolution:
1.68Å     R-factor:   0.191     R-free:   0.236
Authors: L.Englert,A.Heine,G.Klebe
Key ref: L.Englert et al. (2010). Fragment-based lead discovery: screening and optimizing fragments for thermolysin inhibition. ChemMedChem, 5, 930-940. PubMed id: 20394106
Date:
29-Oct-08     Release date:   17-Nov-09    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00800  (THER_BACTH) -  Thermolysin
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+)
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     proteolysis   1 term 
  Biochemical function     metalloendopeptidase activity     1 term  

 

 
ChemMedChem 5:930-940 (2010)
PubMed id: 20394106  
 
 
Fragment-based lead discovery: screening and optimizing fragments for thermolysin inhibition.
L.Englert, K.Silber, H.Steuber, S.Brass, B.Over, H.D.Gerber, A.Heine, W.E.Diederich, G.Klebe.
 
  ABSTRACT  
 
Fragment-based drug discovery has gained a foothold in today's lead identification processes. We present the application of in silico fragment-based screening for the discovery of novel lead compounds for the metalloendoproteinase thermolysin. We have chosen thermolysin to validate our screening approach as it is a well-studied enzyme and serves as a model system for other proteases. A protein-targeted virtual library was designed and screening was carried out using the program AutoDock. Two fragment hits could be identified. For one of them, the crystal structure in complex with thermolysin is presented. This compound was selected for structure-based optimization of binding affinity and improvement of ligand efficiency, while concomitantly keeping the fragment-like properties of the initial hit. Redesigning the zinc coordination group revealed a novel class of fragments possessing K(i) values as low as 128 microM, thus they provide a good starting point for further hit evolution in a tailored lead design.