2ZGJ

Crystal Structure of D86N-GzmM Complexed with Its Optimal Synthesized Substrate


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.288 
  • R-Value Work: 0.240 
  • R-Value Observed: 0.242 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Structural basis for proteolytic specificity of the human apoptosis-inducing granzyme M

Wu, L.Wang, L.Hua, G.Liu, K.Yang, X.Zhai, Y.Bartlam, M.Sun, F.Fan, Z.

(2009) J Immunol 183: 421-429

  • DOI: https://doi.org/10.4049/jimmunol.0803088
  • Primary Citation of Related Structures:  
    2ZGC, 2ZGH, 2ZGJ, 2ZKS

  • PubMed Abstract: 

    Granzyme M (GzmM), a unique serine protease constitutively expressed in NK cells, is important for granule-mediated cytolysis and can induce rapid caspase-dependent apoptosis of tumor cells. However, few substrates of GzmM have been reported to date, and the mechanism by which this enzyme recognizes and hydrolyzes substrates is unknown. To provide structural insights into the proteolytic specificity of human GzmM (hGzmM), crystal structures of wild-type hGzmM, the inactive D86N-GzmM mutant with bound peptide substrate, and the complexes with a catalytic product and with a tetrapeptide chloromethylketone inhibitor were solved to 1.96 A, 2.30 A, 2.17 A and 2.70 A, respectively. Structure-based mutagenesis revealed that the N terminus and catalytic triad of hGzmM are most essential for proteolytic function. In particular, D86N-GzmM was found to be an ideal inactive enzyme for functional studies. Structural comparisons indicated a large conformational change of the L3 loop upon substrate binding, and suggest this loop mediates the substrate specificity of hGzmM. Based on the complex structure of GzmM with its catalytic product, a tetrapeptide chloromethylketone inhibitor was designed and found to specifically block the catalytic activity of hGzmM.


  • Organizational Affiliation

    Center for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Granzyme M240Homo sapiensMutation(s): 1 
Gene Names: GZMMMET1
EC: 3.4.21
UniProt & NIH Common Fund Data Resources
Find proteins for P51124 (Homo sapiens)
Explore P51124 
Go to UniProtKB:  P51124
PHAROS:  P51124
GTEx:  ENSG00000197540 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP51124
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
SSGKVPLS8N/AMutation(s): 0 
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.288 
  • R-Value Work: 0.240 
  • R-Value Observed: 0.242 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.487α = 90
b = 74.487β = 90
c = 112.689γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-01-27
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Advisory, Version format compliance
  • Version 1.2: 2021-11-10
    Changes: Database references, Derived calculations
  • Version 1.3: 2023-11-01
    Changes: Data collection, Refinement description