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PDBsum entry 2m3o
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Peptide binding protein/protein binding
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PDB id
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2m3o
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References listed in PDB file
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Key reference
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Title
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Structure and dynamics of human nedd4-1 ww3 in complex with the αenac py motif.
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Authors
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R.Bobby,
K.Medini,
P.Neudecker,
T.V.Lee,
M.A.Brimble,
F.J.Mcdonald,
J.S.Lott,
A.J.Dingley.
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Ref.
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Biochim Biophys Acta, 2013,
1834,
1632-1641.
[DOI no: ]
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PubMed id
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Abstract
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Nedd4-1 (neuronal precursor cell expressed developmentally downregulated gene
4-1) is an E3 ubiquitin ligase that interacts with and negatively regulates the
epithelial Na(+) channel (ENaC). The WW domains of Nedd4-1 bind to the ENaC
subunits via recognition of PY motifs. Human Nedd4-1 (hNedd4-1) contains four WW
domains with the third domain (WW3*) showing the strongest affinity to the PY
motif. To understand the mechanism underlying this binding affinity, we have
carried out NMR structural and dynamics analyses of the hNedd4-1 WW3* domain in
complex with a peptide comprising the C-terminal tail of the human ENaC
α-subunit. The structure reveals that the peptide interacts in a similar manner
to other WW domain-ENaC peptide structures. Crucial interactions that likely
provide binding affinity are the broad XP groove facilitating additional
contacts between the WW3* domain and the peptide, compared to similar complexes,
and the large surface area buried (83Å(2)) between R430 (WW3*) and L647'
(αENaC). This corroborates the model-free analysis of the (15)N backbone
relaxation data, which showed that R430 is the most rigid residue in the domain
(S(2)=0.90±0.01). Carr-Purcell-Meiboom-Gill relaxation dispersion analysis
identified two different conformational exchange processes on the μs-ms
time-scale. One of these processes involves residues located at the peptide
binding interface, suggesting conformational exchange may play a role in peptide
recognition. Thus, both structural and dynamic features of the complex appear to
define the high binding affinity. The results should aid interpretation of
biochemical data and modeling interfaces between Nedd4-1 and other interacting
proteins.
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