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1P9L

Structure of M. tuberculosis dihydrodipicolinate reductase in complex with NADH and 2,6 PDC

Summary for 1P9L
Entry DOI10.2210/pdb1p9l/pdb
Related1ARZ 1C3V 1DIH
Descriptordihydrodipicolinate reductase, 1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE, PYRIDINE-2,6-DICARBOXYLIC ACID, ... (5 entities in total)
Functional Keywordsoxidoreductase, reductase, lysine biosynthesis, nadh binding specificity, tb structural genomics consortium, tbsgc, structural genomics, psi, protein structure initiative
Biological sourceMycobacterium tuberculosis
Cellular locationCytoplasm (By similarity): P72024
Total number of polymer chains2
Total formula weight53446.11
Authors
Cirilli, M.,Zheng, R.,Scapin, G.,Blanchard, J.S.,TB Structural Genomics Consortium (TBSGC) (deposition date: 2003-05-12, release date: 2003-08-26, Last modification date: 2023-08-16)
Primary citationCirilli, M.,Zheng, R.,Scapin, G.,Blanchard, J.S.
The three-dimensional structures of the Mycobacterium tuberculosis dihydrodipicolinate reductase-NADH-2,6-PDC and -NADPH-2,6-PDC complexes. Structural and mutagenic analysis of relaxed nucleotide specificity.
Biochemistry, 42:10644-10650, 2003
Cited by
PubMed Abstract: Dihydrodipicolinate reductase (DHPR) catalyzes the reduced pyridine nucleotide-dependent reduction of the alpha,beta-unsaturated cyclic imine, dihydrodipicolinate, to generate tetrahydrodipicolinate. This enzyme catalyzes the second step in the bacterial biosynthetic pathway that generates meso-diaminopimelate, a component of bacterial cell walls, and the amino acid L-lysine. The Mycobacterium tuberculosis dapB-encoded DHPR has been cloned, expressed, purified, and crystallized in two ternary complexes with NADH or NADPH and the inhibitor 2,6-pyridinedicarboxylate (2,6-PDC). The structures have been solved using molecular replacement strategies, and the DHPR-NADH-2,6-PDC and DHPR-NADPH-2,6-PDC complexes have been refined against data to 2.3 and 2.5 A, respectively. The M. tuberculosis DHPR is a tetramer of identical subunits, with each subunit composed of two domains connected by two flexible hinge regions. The N-terminal domain binds pyridine nucleotide, while the C-terminal domain is involved in both tetramer formation and substrate/inhibitor binding. The M. tuberculosis DHPR uses NADH and NADPH with nearly equal efficiency based on V/K values. To probe the nature of this substrate specificity, we have generated two mutants, K9A and K11A, residues that are close to the 2'-phosphate of NADPH. These two mutants exhibit decreased specificity for NADPH by factors of 6- and 30-fold, respectively, but the K11A mutant exhibits 270% of WT activity using NADH. The highly conserved structure of the nucleotide fold may permit other enzyme's nucleotide specificity to be altered using similar mutagenic strategies.
PubMed: 12962488
DOI: 10.1021/bi030044v
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.3 Å)
Structure validation

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