1KR2

CRYSTAL STRUCTURE OF HUMAN NMN/NAMN ADENYLYL TRANSFERASE COMPLEXED WITH TIAZOFURIN ADENINE DINUCLEOTIDE (TAD)

Summary for 1KR2

• Entry DOI: 10.2210/pdb1kr2/pdb
• Related: 1KQN 1KQO
• Descriptor: NICOTINAMIDE MONONUCLEOTIDE ADENYLYL TRANSFERASE, BETA-METHYLENE-THIAZOLE-4-CARBOXYAMIDE-ADENINE DINUCLEOTIDE (3 entities in total)
• Functional Keywords: nucleotidyltransferase superfamily, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: Q9HAN9
• Total number of polymer chains: 6
• Total formula weight: 195899.89

Authors

Zhou, T.,Kurnasov, O.,Tomchick, D.R.,Binns, D.D.,Grishin, N.V.,Marquez, V.E.,Osterman, A.L.,Zhang, H. (deposition date: 2002-01-08, release date: 2003-01-08, Last modification date: 2024-04-03)

Primary citation

Zhou, T.,Kurnasov, O.,Tomchick, D.R.,Binns, D.D.,Grishin, N.V.,Marquez, V.E.,Osterman, A.L.,Zhang, H.
Structure of Hhuman of Nicotinamide/Nicotinic Acid Mononucleotide Adenylyltransferase. Basis for the dual substrate specificity and activation of the oncolytic agent tiazofurin.
J.Biol.Chem., 277:13148-13154, 2002

PubMed Abstract: Nicotinamide/nicotinate mononucleotide (NMN/ NaMN)adenylyltransferase (NMNAT) is an indispensable enzyme in the biosynthesis of NAD(+) and NADP(+). Human NMNAT displays unique dual substrate specificity toward both NMN and NaMN, thus flexible in participating in both de novo and salvage pathways of NAD synthesis. Human NMNAT also catalyzes the rate-limiting step of the metabolic conversion of the anticancer agent tiazofurin to its active form tiazofurin adenine dinucleotide (TAD). The tiazofurin resistance is mainly associated with the low NMNAT activity in the cell. We have solved the crystal structures of human NMNAT in complex with NAD, deamido-NAD, and a non-hydrolyzable TAD analogue beta-CH(2)-TAD. These complex structures delineate the broad substrate specificity of the enzyme toward both NMN and NaMN and reveal the structural mechanism for adenylation of tiazofurin nucleotide. The crystal structure of human NMNAT also shows that it forms a barrel-like hexamer with the predicted nuclear localization signal sequence located on the outside surface of the barrel, supporting its functional role of interacting with the nuclear transporting proteins. The results from the analytical ultracentrifugation studies are consistent with the formation of a hexamer in solution under certain conditions.

PubMed: 11788603
DOI: 10.1074/jbc.M111469200

Experimental method

X-RAY DIFFRACTION (2.3 Å)