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PDBsum entry 4gaw
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PDB id:
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Hydrolase
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Title:
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Crystal structure of active human granzyme h
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Structure:
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Granzyme h. Chain: a, b, c, d, e, f, g, h, i, j, k, l. Synonym: ccp-x, cathepsin g-like 2, ctsgl2, cytotoxic t-lymphocyte proteinase, cytotoxic serine proteasE C, csp-c. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: gzmh, cgl2, ctsgl2. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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3.00Å
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R-factor:
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0.272
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R-free:
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0.306
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Authors:
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L.Wang,Q.Li,L.Wu,K.Zhang,L.Tong,F.Sun,Z.Fan
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Key ref:
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L.Wang
et al.
(2013).
Identification of SERPINB1 as a physiological inhibitor of human granzyme H.
J Immunol,
190,
1319-1330.
PubMed id:
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Date:
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25-Jul-12
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Release date:
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16-Jan-13
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PROCHECK
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Headers
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References
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P20718
(GRAH_HUMAN) -
Granzyme H from Homo sapiens
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Seq:
Struc:
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246 a.a.
224 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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J Immunol
190:1319-1330
(2013)
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PubMed id:
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Identification of SERPINB1 as a physiological inhibitor of human granzyme H.
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L.Wang,
Q.Li,
L.Wu,
S.Liu,
Y.Zhang,
X.Yang,
P.Zhu,
H.Zhang,
K.Zhang,
J.Lou,
P.Liu,
L.Tong,
F.Sun,
Z.Fan.
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ABSTRACT
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The granzyme/perforin pathway is a major mechanism for cytotoxic lymphocytes to
eliminate virus-infected and tumor cells. The balance between activation and
inhibition of the proteolytic cascade must be tightly controlled to avoid self
damage. Granzyme H (GzmH) is constitutively expressed in NK cells and induces
target cell death; however, how GzmH activity is regulated remains elusive. We
reported earlier the crystal structures of inactive D102N-GzmH alone and in
complex with its synthetic substrate and inhibitor, as well as defined the
mechanisms of substrate recognition and enzymatic activation. In this study, we
identified SERPINB1 as a potent intracellular inhibitor for GzmH. Upon cleavage
of the reactive center loop at Phe(343), SERPINB1 forms an SDS-stable covalent
complex with GzmH. SERPINB1 overexpression suppresses GzmH- or LAK cell-mediated
cytotoxicity. We determined the crystal structures of active GzmH and SERPINB1
(LM-DD mutant) in the native conformation to 3.0- and 2.9-Å resolution,
respectively. Molecular modeling reveals the possible conformational changes in
GzmH for the suicide inhibition. Our findings provide new insights into the
inhibitory mechanism of SERPINB1 against human GzmH.
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