title: Structural basis for chromosome X-linked agammaglobulinemia: a tyrosine kinase disease.
abstract: X-linked agammaglobulinemia (XLA) is a hereditary defect of B-cell differentiation in man caused by deficiency of Bruton tyrosine kinase (BTK). A three-dimensional model for the BTK kinase domain, based on the core structure of cAMP-dependent protein kinase, was used to interpret the structural basis for disease in eight independent point mutations in patients with XLA. As Arg-525 of BTK has been thought to functionally substitute for a critical lysine residue in protein-serine kinases, the mutation Arg-525-->Gln was studied and found to abrogate the tyrosine kinase activity of BTK. All of the eight mutations (Lys-430-->Glu, Arg-520-->Glu, Arg-525-->Gln, Arg-562-->Pro, Ala-582-->Val, Glu-589-->Gly, Gly-594-->Glu, and Gly-613-->Asp) were located on one face of the BTK kinase domain, indicating structural clustering of functionally important residues.
authors: Center for Structural Biochemistry, Karolinska Institute, NOVUM, Huddinge, Sweden.
authors: M
authors: M
authors: Vihinen
authors: D
authors: D
authors: Vetrie
authors: H S
authors: HS
authors: Maniar
authors: H D
authors: HD
authors: Ochs
authors: Q
authors: Q
authors: Zhu
authors: I
authors: I
authors: Vorechovský
authors: A D
authors: AD
authors: Webster
authors: L D
authors: LD
authors: Notarangelo
authors: L
authors: L
authors: Nilsson
authors: J M
authors: JM
authors: Sowadski
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000361:Agammaglobulinemia / Q000201:enzymology*; D000595:Amino Acid Sequence; D003198:Computer Simulation; D006801:Humans; D008274:Magnesium / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D014960:X Chromosome
chemical_list: D000255:Adenosine Triphosphate; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D008274:Magnesium