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PDBsum entry 3ikl
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* Residue conservation analysis
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PDB id:
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Transferase
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Title:
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Crystal structure of pol gb delta-i4.
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Structure:
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DNA polymerase subunit gamma-2, mitochondrial. Chain: a, b. Synonym: mitochondrial DNA polymerase accessory subunit, polg-beta, mtpolb, DNA polymerase gamma accessory 55 kda subunit, p55. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: polg2, mtpolb
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Resolution:
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3.10Å
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R-factor:
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0.257
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R-free:
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0.294
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Authors:
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Y.S.Lee,W.D.Kennedy,Y.W.Yin
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Key ref:
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Y.S.Lee
et al.
(2009).
Structural insight into processive human mitochondrial DNA synthesis and disease-related polymerase mutations.
Cell,
139,
312-324.
PubMed id:
DOI:
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Date:
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06-Aug-09
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Release date:
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25-Aug-10
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PROCHECK
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Headers
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References
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Q9UHN1
(DPOG2_HUMAN) -
DNA polymerase subunit gamma-2, mitochondrial from Homo sapiens
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Seq:
Struc:
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485 a.a.
364 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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Enzyme class:
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E.C.2.7.7.7
- DNA-directed Dna polymerase.
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Reaction:
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DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + diphosphate
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DNA(n)
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+
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2'-deoxyribonucleoside 5'-triphosphate
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=
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DNA(n+1)
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+
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diphosphate
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Cell
139:312-324
(2009)
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PubMed id:
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Structural insight into processive human mitochondrial DNA synthesis and disease-related polymerase mutations.
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Y.S.Lee,
W.D.Kennedy,
Y.W.Yin.
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ABSTRACT
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Human mitochondrial DNA polymerase (Pol gamma) is the sole replicase in
mitochondria. Pol gamma is vulnerable to nonselective antiretroviral drugs and
is increasingly associated with mutations found in patients with
mitochondriopathies. We determined crystal structures of the human
heterotrimeric Pol gamma holoenzyme and, separately, a variant of its
processivity factor, Pol gammaB. The holoenzyme structure reveals an unexpected
assembly of the mitochondrial DNA replicase where the catalytic subunit Pol
gammaA interacts with its processivity factor primarily via a domain that is
absent in all other DNA polymerases. This domain provides a structural module
for supporting both the intrinsic processivity of the catalytic subunit alone
and the enhanced processivity of holoenzyme. The Pol gamma structure also
provides a context for interpreting the phenotypes of disease-related mutations
in the polymerase and establishes a foundation for understanding the molecular
basis of toxicity of anti-retroviral drugs targeting HIV reverse transcriptase.
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Selected figure(s)
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Figure 1.
Figure 1. Structure of Pol γ
(A) Structure of Pol γA.
The pol domain shows a canonical “right-hand” configuration
with thumb (green), palm (red), and fingers (blue) subdomains
and the exo domain (gray). The spacer domain (orange) presents a
unique structure and is divided into two subdomains. Domains are
shown in a linear form where the N-terminal domain contains
residues 1–170; exo, 171–440; spacer, 476–785; and pol,
441–475 and 786–1239. All figures are made with Pymol
(DeLano, 2002).
(B and C) Structure of the heterotrimeric
Pol γ holoenzyme containing one catalytic subunit Pol γA
(orange) and the proximal (green) and distal (blue) monomers of
Pol γB. Pol γA primarily interacts with the proximal monomer
of the dimeric Pol γB.
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Figure 2.
Figure 2. The Major Pol γ Subunit Interfaces
(A–C)
Pol γA- Pol γB proximal monomer interactions. The distal
monomer is omitted for clarity.
(A) Charge-charge
interactions between the thumb domain of Pol γA and the
C-terminal domain of Pol γB.
(B) L-shaped support between
Pol γA and the proximal monomer of Pol γB.
(C)
Hydrophobic interactions between the L helix of Pol γA and a
hydrophobic core of Pol γB. Mutated residues L^549, L^552, and
K^553 are shown.
(D) Sequence alignments of residues
involved in hydrophobic interactions between Pol γA and Pol
γB.
(E–G) Pol γA- Pol γB distal monomer interactions.
The proximal monomer is omitted for clarity.
(E) The
salt-bridge (2.8 Å) between Pol γA R^232 and the distal
Pol γB E^394.
(F) Pol γA-Pol γB distal monomer.
(G)
The weak van der Waals interaction (5.3 Å) between Pol γA
and the distal Pol γB monomer.
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The above figures are
reprinted
by permission from Cell Press:
Cell
(2009,
139,
312-324)
copyright 2009.
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Figures were
selected
by an automated process.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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J.D.Stumpf,
and
W.C.Copeland
(2011).
Mitochondrial DNA replication and disease: insights from DNA polymerase γ mutations.
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Cell Mol Life Sci,
68,
219-233.
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N.Atanassova,
J.M.Fusté,
S.Wanrooij,
B.Macao,
S.Goffart,
S.Bäckström,
G.Farge,
I.Khvorostov,
N.G.Larsson,
J.N.Spelbrink,
and
M.Falkenberg
(2011).
Sequence-specific stalling of DNA polymerase γ and the effects of mutations causing progressive ophthalmoplegia.
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Hum Mol Genet,
20,
1212-1223.
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Y.W.Yin
(2011).
Structural insight on processivity, human disease and antiviral drug toxicity.
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Curr Opin Struct Biol,
21,
83-91.
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C.M.Bailey,
and
K.S.Anderson
(2010).
A mechanistic view of human mitochondrial DNA polymerase gamma: providing insight into drug toxicity and mitochondrial disease.
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Biochim Biophys Acta,
1804,
1213-1222.
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E.Johansson,
and
S.A.Macneill
(2010).
The eukaryotic replicative DNA polymerases take shape.
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Trends Biochem Sci,
35,
339-347.
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J.D.Stumpf,
C.M.Bailey,
D.Spell,
M.Stillwagon,
K.S.Anderson,
and
W.C.Copeland
(2010).
mip1 Containing mutations associated with mitochondrial disease causes mutagenesis and depletion of mtDNA in Saccharomyces cerevisiae.
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Hum Mol Genet,
19,
2123-2133.
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K.Szczepanowska,
and
F.Foury
(2010).
A cluster of pathogenic mutations in the 3'-5' exonuclease domain of DNA polymerase gamma defines a novel module coupling DNA synthesis and degradation.
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Hum Mol Genet,
19,
3516-3529.
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M.T.Oliveira,
and
L.S.Kaguni
(2010).
Functional roles of the N- and C-terminal regions of the human mitochondrial single-stranded DNA-binding protein.
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PLoS One,
5,
e15379.
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R.P.Saneto,
and
R.K.Naviaux
(2010).
Polymerase gamma disease through the ages.
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Dev Disabil Res Rev,
16,
163-174.
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Y.S.Lee,
S.Lee,
B.Demeler,
I.J.Molineux,
K.A.Johnson,
and
Y.W.Yin
(2010).
Each monomer of the dimeric accessory protein for human mitochondrial DNA polymerase has a distinct role in conferring processivity.
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J Biol Chem,
285,
1490-1499.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
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Links
