title: Solution structure of GAP SH3 domain by 1H NMR and spatial arrangement of essential Ras signaling-involved sequence.
abstract: Src homology 3 (SH3) domains are found in numerous cytoplasmic proteins involved in intracellular signal transduction. We used 2-D 1H NMR to determine the structure of the SH3 domain of the guanosine triphosphatase-activating protein (GAP), an essential component of the Ras signaling pathway. The structure of the GAP SH3 domain (275-350) was found to be a compact beta-barrel made of six antiparallel beta-strands arranged in two roughly perpendicular beta-sheets with the acidic residues located at the surface of the protein. The Trp317, Trp319, Thr321 and Leu323 residues belonging to the sequence (317-326), which was shown to be essential for Ras signaling, formed two nearby lipophilic bulges followed by a hydrophilic domain (Arg324-Asp326). These structural data could be used to characterize the still unidentified downstream components of GAP, which are involved in Ras signaling, and to rationally design inhibitors of this pathway.
authors.affiliation: Département de Pharmacochimie Moléculaire et Structurale, U266 INSERM-URA D1500 CNRS, Faculté de Pharmacie, France.
authors.forename: Y S
authors.initials: YS
authors.lastname: Yang
authors.forename: C
authors.initials: C
authors.lastname: Garbay
authors.forename: M
authors.initials: M
authors.lastname: Duchesne
authors.forename: F
authors.initials: F
authors.lastname: Cornille
authors.forename: N
authors.initials: N
authors.lastname: Jullian
authors.forename: N
authors.initials: N
authors.lastname: Fromage
authors.forename: B
authors.initials: B
authors.lastname: Tocque
authors.forename: B P
authors.initials: BP
authors.lastname: Roques
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D003196:Computer Graphics; D020690:GTPase-Activating Proteins; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D015689:Oncogene Protein p21(ras) / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D011522:Protons; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D020703:ras GTPase-Activating Proteins
chemical_list: D020690:GTPase-Activating Proteins; D008024:Ligands; D011506:Proteins; D011522:Protons; D020703:ras GTPase-Activating Proteins; D015689:Oncogene Protein p21(ras)