Bruton's tyrosine kinase (Btk) of the Tec family possesses a Pleckstrin homology (PH) domain, which is responsible for plasma membrane targeting, In this Study, the crystal Structure of the Btk PH domain in complex with dibutylyl-phosphatidylinositol-3,4,5-triphosphate was determined. The structure revealed that the Btk PH domain forms a homodimer and that each molecule binds phosphatidylinositol in the binding pocket. The side chain of Lysl 8 within a Btk-specific insertion in the beta 1-beta 2 loop is able to form a hydrol-en bond with the diacylglycerol moiety of phosphatidylinositol. The other Btk-specific insertion in the beta 5-beta 6 loop constitutes the dimerization interface. Thus, the modes of phosphatidylinositol recognition and Btk PH domain dimerization are distinct from those of other PH domains. (C) 2008 Elsevier Inc. All rights reserved.