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PDBsum entry 1awx
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References listed in PDB file
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Key reference
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Title
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Solution structure of the sh3 domain from bruton'S tyrosine kinase.
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Authors
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H.Hansson,
P.T.Mattsson,
P.Allard,
P.Haapaniemi,
M.Vihinen,
C.I.Smith,
T.Hard.
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Ref.
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Biochemistry, 1998,
37,
2912-2924.
[DOI no: ]
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PubMed id
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Abstract
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X-linked agammaglobulinemia (XLA) is a heritable immunodeficiency caused by
mutations in the gene coding for Bruton's tyrosine kinase (Btk). Btk belongs to
the Tec family of tyrosine kinases. Each member of the family contains five
regions and mutations causing XLA have been isolated in all five regions. We
have determined the solution structure of the Src homology 3 (SH3) domain of Btk
using two- and three-dimensional nuclear magnetic resonance (NMR) spectroscopy
on natural abundance and 15N-labeled protein material. The structure
determination is complemented by investigation of backbone dynamics based on 15N
NMR relaxation. The Btk SH3 forms a well-defined structure and shows the typical
SH3 topology of two short antiparallel beta-sheets packed almost perpendicular
to each other in a sandwich-like fold. The N- and C-termini are more flexible as
are peptide fragments in the RT and n-Src loops. The studied Btk SH3 fragment
adopts two slowly interconverting conformations with a relative concentration
ratio of 7:1. The overall fold of the minor form is similar to that of the major
form, as judged on the basis of observed NOE connectivities and small chemical
shift differences. A tryptophan (W251) ring flip is the favored mechanism for
interconversion, although other possibilities cannot be excluded. The side chain
of Y223, which becomes autophosphorylated upon activation of Btk, is exposed
within the potential SH3 ligand binding site. Finally, we compare the present
Btk SH3 structure with other SH3 structures.
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