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PDBsum entry 2zo1
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References listed in PDB file
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Key reference
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Title
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The sra domain of uhrf1 flips 5-Methylcytosine out of the DNA helix.
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Authors
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H.Hashimoto,
J.R.Horton,
X.Zhang,
M.Bostick,
S.E.Jacobsen,
X.Cheng.
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Ref.
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Nature, 2008,
455,
826-829.
[DOI no: ]
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PubMed id
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Abstract
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Maintenance methylation of hemimethylated CpG dinucleotides at DNA replication
forks is the key to faithful mitotic inheritance of genomic methylation
patterns. UHRF1 (ubiquitin-like, containing PHD and RING finger domains 1) is
required for maintenance methylation by interacting with DNA nucleotide
methyltransferase 1 (DNMT1), the maintenance methyltransferase, and with
hemimethylated CpG, the substrate for DNMT1 (refs 1 and 2). Here we present the
crystal structure of the SET and RING-associated (SRA) domain of mouse UHRF1 in
complex with DNA containing a hemimethylated CpG site. The DNA is contacted in
both the major and minor grooves by two loops that penetrate into the middle of
the DNA helix. The 5-methylcytosine has flipped completely out of the DNA helix
and is positioned in a binding pocket with planar stacking contacts,
Watson-Crick polar hydrogen bonds and van der Waals interactions specific for
5-methylcytosine. Hence, UHRF1 contains a previously unknown DNA-binding module
and is the first example of a non-enzymatic, sequence-specific DNA-binding
protein domain to use the base flipping mechanism to interact with DNA.
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Figure 1.
Figure 1: Structure of SRA–DNA complex. a, Summary of the
SRA–DNA interactions; mc, main-chain-atom-mediated contacts;
w, water-mediated hydrogen bonds. Black boxes represent CpG
recognition sequence and K495-associated dotted lines represent
weak hydrogen bonds. b, The side chains of V451 of the base
flipping loop and R496 of the CpG recognition loop are in direct
van der Waals contact. c, The two loops—CpG recognition and
base flipping—penetrate into the DNA helix from opposite
directions. d, The 5mC flips out and binds in a cage-like
pocket. e, The surface charge at neutral pH is displayed as blue
for positive (20 k[B]T), red for negative (-20 k[B]T), and white
for neutral, where k[B] is the Boltzmann's constant and T is the
temperature.
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Figure 2.
Figure 2: Details of SRA–DNA interactions. a, The 5mC  G
base pair is shown in the front, and the adjoining G C
base pair is in the back. b, Planar stacking contacts of the
extrahelical 5mC with Y471 and Y483 (left image). Omit electron
densities, contoured at 4  and
5 above
the mean, respectively, are shown for omitting 5mC (blue) or the
methyl group (red) (right image). c, The hydrogen bond
interactions with the polar atoms of 5mC. The double-dotted
lines indicate van der Waals contacts with the methyl group of
ring carbon C5. d, H450 forms a hydrogen bond from the minor
groove side with cytosine of G C
pair at position 5 (see Fig. 1a). e, Network of internal polar
interactions centred on residues H447 and S464. Gua, guanine. f,
Network of internal charged interactions centred on residues
R541 and D560. Distances are shown in angstroms.
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The above figures are
reprinted
from an Open Access publication published by Macmillan Publishers Ltd:
Nature
(2008,
455,
826-829)
copyright 2008.
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