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PDBsum entry 6dw3
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Hydrolase/hydrolase inhibitor
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PDB id
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6dw3
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PDB id:
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| Name: |
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Hydrolase/hydrolase inhibitor
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Title:
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Samhd1 bound to cytarabine-tp in the catalytic pocket
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Structure:
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Deoxynucleoside triphosphate triphosphohydrolase samhd1. Chain: d, c, b, a. Synonym: dntpase,dendritic cell-derived ifng-induced protein,dcip, monocyte protein 5,mop-5,sam domain and hd domain-containing protein 1. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: samhd1, mop5. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008
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Resolution:
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2.20Å
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R-factor:
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0.192
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R-free:
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0.228
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Authors:
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K.M.Knecht,O.Buzovetsky,C.Schneider,D.Thomas,V.Srikanth,L.Kaderali, F.Tofoleanu,K.Reiss,N.Ferreiros,G.Geisslinger,V.S.Batista,X.Ji, J.Cinatl,O.T.Keppler,Y.Xiong
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Key ref:
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K.M.Knecht
et al.
(2018).
The structural basis for cancer drug interactions with the catalytic and allosteric sites of SAMHD1.
Proc Natl Acad Sci U S A,
115,
E10022.
PubMed id:
DOI:
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Date:
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26-Jun-18
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Release date:
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10-Oct-18
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PROCHECK
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Headers
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References
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Q9Y3Z3
(SAMH1_HUMAN) -
Deoxynucleoside triphosphate triphosphohydrolase SAMHD1 from Homo sapiens
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Seq:
Struc:
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626 a.a.
480 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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*
PDB and UniProt seqs differ
at 2 residue positions (black
crosses)
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DOI no:
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Proc Natl Acad Sci U S A
115:E10022
(2018)
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PubMed id:
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The structural basis for cancer drug interactions with the catalytic and allosteric sites of SAMHD1.
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K.M.Knecht,
O.Buzovetsky,
C.Schneider,
D.Thomas,
V.Srikanth,
L.Kaderali,
F.Tofoleanu,
K.Reiss,
N.Ferreirós,
G.Geisslinger,
V.S.Batista,
X.Ji,
J.Cinatl,
O.T.Keppler,
Y.Xiong.
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ABSTRACT
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SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase (dNTPase) that
depletes cellular dNTPs in noncycling cells to promote genome stability and to
inhibit retroviral and herpes viral replication. In addition to being
substrates, cellular nucleotides also allosterically regulate SAMHD1 activity.
Recently, it was shown that high expression levels of SAMHD1 are also correlated
with significantly worse patient responses to nucleotide analog drugs important
for treating a variety of cancers, including acute myeloid leukemia (AML). In
this study, we used biochemical, structural, and cellular methods to examine the
interactions of various cancer drugs with SAMHD1. We found that both the
catalytic and the allosteric sites of SAMHD1 are sensitive to sugar
modifications of the nucleotide analogs, with the allosteric site being
significantly more restrictive. We crystallized cladribine-TP, clofarabine-TP,
fludarabine-TP, vidarabine-TP, cytarabine-TP, and gemcitabine-TP in the
catalytic pocket of SAMHD1. We found that all of these drugs are substrates of
SAMHD1 and that the efficacy of most of these drugs is affected by SAMHD1
activity. Of the nucleotide analogs tested, only cladribine-TP with a
deoxyribose sugar efficiently induced the catalytically active SAMHD1 tetramer.
Together, these results establish a detailed framework for understanding the
substrate specificity and allosteric activation of SAMHD1 with regard to
nucleotide analogs, which can be used to improve current cancer and antiviral
therapies.
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Links
