2ZTW

Structure of 3-isopropylmalate dehydrogenase in complex with the inhibitor and NAD+

Summary for 2ZTW

• Entry DOI: 10.2210/pdb2ztw/pdb
• Descriptor: 3-isopropylmalate dehydrogenase, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, (2Z)-2-hydroxy-3-(methylsulfanyl)prop-2-enoic acid, ... (5 entities in total)
• Functional Keywords: 3-isopropylmalate dehydrogenase, ipmdh, decarboxylating dehydrogenase, leucine biosynthesis, amino-acid biosynthesis, branched-chain amino acid biosynthesis, cytoplasm, magnesium, manganese, metal-binding, nad, oxidoreductase
• Biological source: Thermus thermophilus
• Cellular location: Cytoplasm: Q5SIY4
• Total number of polymer chains: 1
• Total formula weight: 37647.04

Authors

Nango, E.,Kumasaka, T.,Eguchi, T. (deposition date: 2008-10-10, release date: 2009-10-13, Last modification date: 2023-11-01)

Primary citation

Nango, E.,Yamamoto, T.,Kumasaka, T.,Eguchi, T.
Crystal structure of 3-isopropylmalate dehydrogenase in complex with NAD(+) and a designed inhibitor
Bioorg.Med.Chem., 17:7789-7794, 2009

PubMed Abstract: Isopropylmalate dehydrogenase (IPMDH) is the third enzyme specific to leucine biosynthesis in microorganisms and plants, and catalyzes the oxidative decarboxylation of (2R,3S)-3-isopropylmalate to alpha-ketoisocaproate using NAD(+) as an oxidizing agent. In this study, a thia-analogue of the substrate was designed and synthesized as an inhibitor for IPMDH. The analogue showed strong competitive inhibitory activity with K(i)=62nM toward IPMDH derived from Thermus thermophilus. Moreover, the crystal structure of T. thermophilus IPMDH in a ternary complex with NAD(+) and the inhibitor has been determined at 2.8A resolution. The inhibitor exists as a decarboxylated product with an enol/enolate form in the active site. The product interacts with Arg 94, Asn 102, Ser 259, Glu 270, and a water molecule hydrogen-bonding with Arg 132. All interactions between the product and the enzyme were observed in the position associated with keto-enol tautomerization. This result implies that the tautomerization step of the thia-analogue during the IPMDH reaction is involved in the inhibition.

PubMed: 19833522
DOI: 10.1016/j.bmc.2009.09.025

Experimental method

X-RAY DIFFRACTION (2.79 Å)