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PDBsum entry 3ikl
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References listed in PDB file
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Key reference
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Title
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Structural insight into processive human mitochondrial DNA synthesis and disease-Related polymerase mutations.
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Authors
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Y.S.Lee,
W.D.Kennedy,
Y.W.Yin.
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Ref.
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Cell, 2009,
139,
312-324.
[DOI no: ]
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PubMed id
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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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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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