1TMN

Binding of n-carboxymethyl dipeptide inhibitors to thermolysin determined by x-ray crystallography. a novel class of transition-state analogues for zinc peptidases

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Work: 0.171 

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Literature

Binding of N-carboxymethyl dipeptide inhibitors to thermolysin determined by X-ray crystallography: a novel class of transition-state analogues for zinc peptidases

Monzingo, A.F., Matthews, B.W.

(1984) Biochemistry 23: 5724-5729

  • DOI: https://doi.org/10.1021/bi00319a010
  • Primary Citation of Related Structures:  
    1TMN

  • PubMed 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)


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
THERMOLYSINA [auth E]316Bacillus thermoproteolyticusMutation(s): 0 
Gene Names: npr
EC: 3.4.24.27
UniProt
Find proteins for P00800 (Bacillus thermoproteolyticus)
Explore P00800 
Go to UniProtKB:  P00800
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00800
Sequence Annotations
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  • Reference Sequence
Biologically Interesting Molecules (External Reference) 1 Unique
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Work: 0.171 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 94.2α = 90
b = 94.2β = 90
c = 131.4γ = 120
Software Package:
Software NamePurpose
EREFrefinement
OSCTSTdata reduction
AGROVATA/ROTAVATEdata scaling
RICHARDSphasing

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 1989-01-09
    Type: Initial release
  • Version 1.1: 2008-03-03
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Advisory, Atomic model, Database references, Derived calculations, Non-polymer description, Structure summary, Version format compliance
  • Version 1.3: 2012-12-12
    Changes: Other
  • Version 1.4: 2017-11-29
    Changes: Derived calculations, Other
  • Version 2.0: 2022-11-23
    Type: Remediation
    Changes: Advisory, Atomic model, Data collection, Database references, Derived calculations, Other