X-RAY STRUCTURE OF HUMAN NUCLEOSIDE DIPHOSPHATE KINASE-B COMPLEXED WITH GDP AT 2-ANGSTROM RESOLUTION

Background: Nucleoside diphosphate (NDP) kinases provide precursors fo r DNA and RNA synthesis. In mammals, these enzymes are also involved i n cell regulations. Human NDP kinase B, product of the human nm23-H2 g ene, is both an enzyme and a transcription factor. it activates transc ription of the c-myc oncogene independently of its catalytic function, by binding to its promoter DNA. How do the mio functions coexist? Res ults: Recombinant human NDP kinase B was co-crystallized with GDP. The X-ray structure was solved at 2.0 Angstrom resolution by molecular re placement from the homologous Drosophila Awd protein. Both enzymes are homo-hexamers with a characteristic beta alpha beta beta alpha beta f old. GDP binds near the active site His118. The guanine base is in a s urface cleft and interacts with the C terminus of another subunit. Con clusions: The beta alpha beta beta alpha beta fold, also present in th e 'palm' domain of Escherichia coli DNA polymerase I and HIV reverse t ranscriptase, is both a mononucleotide- and a polynucleotide-binding f old. If NDP kinase B binds DNA in the same way as the polymerases, the enzyme must undergo a conformation change in order to carry out gene activation.