Crystal structure of human nucleoside diphosphate kinase A, a metastasis suppressor

. Nucleoside diphosphate kinase (NDK) catalyzes the transfer of the g-phosphoryl group from a nucleoside triphosphate (NTP) to a nucleoside diphosphate (NDP) by using ATP as a major phosphate donor. During the catalytic reaction, the enzyme is transiently phosphorylated on a conserved histidine residue. NDP kinases play a primary role in maintaining cellular pools of all NTPs but also in the regulation of important cellular processes. In humans, the two isoforms NDK-A (NM23-H1) and NDK-B (NM23-H2) are closely related in amino acid sequence (88% identity) but display significant differences in cellular functions. NDK-A acts as a metastasis suppressor for some tumor types. NDK-B, also known as PuF, binds to the promoter of the c-myc oncogene and activates its transcription. These cellular functions of the two isoforms are independent of their NDP kinase activity, and two isoforms can form homoand heterohexamers, resulting in different ratios of the respective subunits. We present here the crystal structure of human NDK-A determined at 2.2 Å resolution. This enables a detailed structural comparison of NDK-A with NDK-B, contributing to understanding the difference in their cellular functions.