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PDBsum entry 3d2s
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Metal binding protein/RNA
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PDB id
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3d2s
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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 insights into RNA recognition by the alternative-Splicing regulator muscleblind-Like mbnl1.
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Authors
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M.Teplova,
D.J.Patel.
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Ref.
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Nat Struct Biol, 2008,
15,
1343-1351.
[DOI no: ]
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PubMed id
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Abstract
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Muscleblind-like (MBNL) proteins, regulators of developmentally programmed
alternative splicing, harbor tandem CCCH zinc-finger (ZnF) domains that target
pre-mRNAs containing YGCU(U/G)Y sequence elements (where Y is a pyrimidine). In
myotonic dystrophy, reduced levels of MBNL proteins lead to aberrant alternative
splicing of a subset of pre-mRNAs. The crystal structure of MBNL1 ZnF3/4 bound
to r(CGCUGU) establishes that both ZnF3 and ZnF4 target GC steps, with
site-specific recognition mediated by a network of hydrogen bonds formed
primarily with main chain groups of the protein. The relative alignment of ZnF3
and ZnF4 domains is dictated by the topology of the interdomain linker, with a
resulting antiparallel orientation of bound GC elements, supportive of a
chain-reversal loop trajectory for MBNL1-bound pre-mRNA targets. We anticipate
that MBNL1-mediated targeting of looped RNA segments proximal to splice-site
junctions could contribute to pre-mRNA alternative-splicing regulation.
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Figure 3.
(a) Ribbon and stick representation of the complex containing
one MBNL1 ZnF3/4 domain (molecule A) and three RNAs bound by
ZnF3 and ZnF4. The ZnF3/4 molecule A is colored light blue.
Cysteine and histidine residues coordinating zinc atoms are
shown in ball-and-stick representation. The two symmetry-related
RNA strands are colored pink and the third RNA strand is colored
light orange. The G5 and 5'-C1 nucleotides originating from two
RNA strands are bound to ZnF3, whereas the G2-C3-U4 segment of
the third strand is bound to the ZnF4 motif. (b) An
electrostatic view of the molecule A complex generated using the
GRASP and PyMol programs. Basic and acidic regions appear in
blue and red, with the intensity of the color proportional to
the local potential. (c) View of the protein-RNA interface
highlighting intermolecular contacts between G2-C3-U4 segment
and MBNL1 ZnF4. Stacking interactions of G2 and C3 bases with
arginine and aromatic residues, as well as hydrogen-bonding
contacts involving G2, C3 and U4, are highlighted. (d)
Electrostatic surface representation of the protein-RNA
interface in the same view as in c.
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Figure 4.
(a) Hydrogen-bonding of the N^2 and N^1 of G5 with the side
chain thiols of zinc-bound Cys185 and Cys200 and the O^6 of G5
with the backbone amide of Arg201 of the molecule A ZnF3 motif.
G5 stacks with Arg195 of the ZnF3 motif.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Struct Biol
(2008,
15,
1343-1351)
copyright 2008.
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