6htf

Crystal structure of human Btk SH2 domain bound to rF10 repebody

spinqualitylabelsall models 6htf, resolution 2.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.102Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Bruton's tyrosine kinase (Btk) is critical for B-cell maturation and activation. Btk loss-of-function mutations cause human X-linked agammaglobulinemia (XLA). In contrast, Btk signaling sustains growth of several B-cell neoplasms which may be treated with tyrosine kinase inhibitors (TKIs). Here, we uncovered the structural mechanism by which certain XLA mutations in the SH2 domain strongly perturb Btk activation. Using a combination of molecular dynamics (MD) simulations and small-angle X-ray scattering (SAXS), we discovered an allosteric interface between the SH2 and kinase domain required for Btk activation and to which multiple XLA mutations map. As allosteric interactions provide unique targeting opportunities, we developed an engineered repebody protein binding to the SH2 domain and able to disrupt the SH2-kinase interaction. The repebody prevents activation of wild-type and TKI-resistant Btk, inhibiting Btk-dependent signaling and proliferation of malignant B-cells. Therefore, the SH2-kinase interface is critical for Btk activation and a targetable site for allosteric inhibition. Btk SH2-kinase interface is critical for allosteric kinase activation and its targeting inhibits B-cell neoplasms.,Duarte DP, Lamontanara AJ, La Sala G, Jeong S, Sohn YK, Panjkovich A, Georgeon S, Kukenshoner T, Marcaida MJ, Pojer F, De Vivo M, Svergun D, Kim HS, Dal Peraro M, Hantschel O Nat Commun. 2020 May 8;11(1):2319. doi: 10.1038/s41467-020-16128-5. PMID:32385234 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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