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PDBsum entry 2zgh
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Contents |
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* Residue conservation analysis
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PDB id:
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Hydrolase
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Title:
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Crystal structure of active granzyme m bound to its product
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Structure:
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Granzyme m. Chain: a. Synonym: met-ase, natural killer cell granular protease, hu-met-1, met-1 serine protease. Engineered: yes. Ssgkvpl. Chain: b. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: gzmm, met1. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: peptide synthesis
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Resolution:
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2.17Å
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R-factor:
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0.214
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R-free:
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0.250
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Authors:
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L.F.Wu,L.Wang,G.Q.Hua,K.Liu,Y.J.Zhai,F.Sun,Z.S.Fan
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Key ref:
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L.Wu
et al.
(2009).
Structural basis for proteolytic specificity of the human apoptosis-inducing granzyme M.
J Immunol,
183,
421-429.
PubMed id:
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Date:
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22-Jan-08
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Release date:
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27-Jan-09
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PROCHECK
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Headers
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References
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P51124
(GRAM_HUMAN) -
Granzyme M from Homo sapiens
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Seq:
Struc:
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257 a.a.
231 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
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J Immunol
183:421-429
(2009)
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PubMed id:
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Structural basis for proteolytic specificity of the human apoptosis-inducing granzyme M.
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L.Wu,
L.Wang,
G.Hua,
K.Liu,
X.Yang,
Y.Zhai,
M.Bartlam,
F.Sun,
Z.Fan.
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ABSTRACT
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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.
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Links
