3ASJ: Crystal Structure Of Homoisocitrate Dehydrogenase In Complex With A Designed Inhibitor

Homoisocitrate dehydrogenase (HICDH) is involved in the alpha-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 A 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 A 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.
PDB ID: 3ASJDownload
MMDB ID: 93645
PDB Deposition Date: 2010/12/13
Updated in MMDB: 2011/09
Experimental Method:
x-ray diffraction
Resolution: 2.6  Å
Source Organism:
Similar Structures:
Biological Unit for 3ASJ: tetrameric; determined by author and by software (PISA)
Molecular Components in 3ASJ
Label Count Molecule
Proteins (4 molecules)
Homoisocitrate Dehydrogenase
Molecule annotation
Chemicals (22 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB