The Crystal Structure of A. Cou Dhpr in Complex With Nadh and the Inhibitor 2,6-Pyridine Dicarboxylate
Document Type
Article
Publication Date
12-1-1997
Description
Dihydrodipicolinate reductase (DHPR) catalyzes the NAD(P)H dependent reduction of the rv.-4-unsaîurated cyclic iminc dihydrodipicolinate to form tetrahvdrodipicolinate. The enzyme is a component of the biosynthetic pathway that leads to diaminopimelatc and lysine in bacteria and higher plants. Because these pathways are unique lo microorganisms, they may represent attractive targets for new antimicrobial or herbicidal compounds. The crystal structure of the complex of E. co/i'DHPR with NADH and the inhibitor 2,6-pyridine dicarboxylate has been solved using molecular replacement procedures, and refined against 2.6 A resolution data lo a crvstallographic R-factor of 21.0% (R/rcr is 29.7%). The native enzyme is a 120 K Da t et ramer of idenliral subunit. Kach subunit consists of two domains connected by two flexible hinge regions. While three of the four subunits have a closed conformation, in which the nicotinamid".' ring of the cofactor and the reducible carbon of the substrate are about :î A away, the fourth subunit is unliganded and in an open conformation, suggesting that the enJ.yme undergoes a distinct conformational change upon binding of both substrates. The residues involved in binding of the inhibitor and in catalysis have been identified on the basis of this structure. Site directed mutants have been prepared to further characterize the role of th-4sc residues. I he structure provides in.sights into the catalytic mechanism and substrate specificity and offers the possibility of dcvelopping novel inhibitors based on the knowledge of the active site architecture. Supported by NIH Crant AlüÜti'tr.
Citation Information
Scapin, G.; and Ready, S. Ci. 1997. The Crystal Structure of A. Cou Dhpr in Complex With Nadh and the Inhibitor 2,6-Pyridine Dicarboxylate. FASEB Journal. Vol.11(9). ISSN: 0892-6638