Three-dimensional structure of an oncogene protein: catalytic domain of human c-H-ras p21.
The crystal structure at 2.7 A resolution of the normal human c-H-ras oncogene protein lacking a flexible carboxyl-terminal 18 residue reveals that the protein consists of a six-stranded beta sheet, four alpha helices, and nine connecting loops. Four loops are involved in interactions with bound guanosine diphosphate: one with the phosphates, another with the ribose, and two with the guanine base. Most of the transforming proteins (in vivo and in vitro) have single amino acid substitutions at one of a few key positions in three of these four loops plus one additional loop. The biological functions of the remaining five loops and other exposed regions are at present unknown. However, one loop corresponds to the binding site for a neutralizing monoclonal antibody and another to a putative "effector region"; mutations in the latter region do not alter guanine nucleotide binding or guanosine triphosphatase activity but they do reduce the transforming activity of activated proteins. The data provide a structural basis for understanding the known biochemical properties of normal as well as activated ras oncogene proteins and indicate additional regions in the molecule that may possibly participate in other cellular functions.
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000276:immunology; D001665:Binding Sites; D002384:Catalysis; D003460:Crystallization; D000939:Epitopes / Q000276:immunology; D004926:Escherichia coli / Q000235:genetics; D020558:GTP Phosphohydrolases; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics; D010710:Phosphates / Q000378:metabolism; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D011994:Recombinant Proteins / Q000378:metabolism; D014961:X-Ray Diffraction
D000911:Antibodies, Monoclonal; D000939:Epitopes; D010710:Phosphates; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D020558:GTP Phosphohydrolases; D016283:Proto-Oncogene Proteins p21(ras)