Structure of Thermus thermophilus homoisocitrate dehydrogenase in complex with a designed inhibitor

Eriko Nango, Takashi Yamamoto, Takashi Kumasaka, Tadashi Eguchi

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)


Homoisocitrate dehydrogenase (HICDH) is involved in the α-aminoadipate pathway of lysine biosynthesis in some bacteria and higher fungi, and catalyses the oxidative decarboxylation of (2R,3S)-homoisocitrate into 2-ketoadipate using NAD + as a coenzyme. In this study, the crystal structure of Thermus thermophilus HICDH in a binary complex with a designed inhibitor, (2S,3S)-thiahomoisocitrate, has been determined at 2.6 resolution. The inhibitor observed as a decarboxylated product interacts through hydrogen bonding to Arg 118, Tyr 125 and Lys 171 in the active site. The induced fitting was also observed around the region consisting of residues 120-141, which shifted up to 2.8 towards the active site. In addition, it was found that the complex structure adopts a closed conformation in two domains. While the structure of apo-HICDH shows that a catalytic residue Tyr 125 and Arg 85 that engages in substrate recognition are flipped out of the active site, these residues turn towards the active site in the complex structure. The results revealed that they directly interact with a substrate and are involved in catalysis or substrate recognition. Furthermore, by comparing the binary complex with the quaternary complex of Escherichia coli isocitrate dehydrogenase, the substrate recognition mechanism of HICDH is also discussed.

Original languageEnglish
Pages (from-to)607-614
Number of pages8
JournalJournal of biochemistry
Issue number6
Publication statusPublished - 2011 Dec
Externally publishedYes


  • crystal structure
  • homoisocitrate dehydrogenase
  • inhibitor
  • lysine biosynthesis
  • α-aminoadipate pathway

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology


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