Structural determinants for ligand binding and catalysis of 
triosephosphate isomerase

• Published in: European journal of biochemistry Vol. 268; no. 19; pp. 5189 - 5196
• Main Authors: Kursula, Inari, Partanen, Sanna, Lambeir, Anne‐Marie, Antonov, Dmitry M., Augustyns, Koen, Wierenga, Rik K.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.10.2001
• Subjects: Aminoethylphosphonic Acid - analogs & derivatives; Aminoethylphosphonic Acid - metabolism; Animals; Asparagine - metabolism; Catalysis; Crystallography, X-Ray; Enzyme Inhibitors - pharmacology; hydroxamate; Leishmania - enzymology; Ligands; Models, Molecular; Organophosphonates; oxyanion hole; Protein Conformation; Substrate Specificity; TIM; transition state analogue; Triose-Phosphate Isomerase - antagonists & inhibitors; Triose-Phosphate Isomerase - chemistry; Triose-Phosphate Isomerase - isolation & purification; Triose-Phosphate Isomerase - metabolism
• ISSN: 0014-2956; 1432-1033
• DOI: 10.1046/j.0014-2956.2001.02452.x

The crystal structure of leishmania triosephosphate isomerase (TIM) complexed with 2‐(N‐formyl‐N‐hydroxy)‐aminoethyl phosphonate (IPP) highlights the importance of Asn11 for binding and catalysis. IPP is an analogue of the substrate d‐glyceraldehyde‐3‐phosphate, and it is observed to bind with its aldehyde oxygen in an oxyanion hole formed by ND2 of Asn11 and NE2 of His95. Comparison of the mode of binding of IPP and the transition state analogue phosphoglycolohydroxamate (PGH) suggests that the Glu167 side chain, as well as the triose part of the substrate, adopt different conformations as the catalysed reaction proceeds. Comparison of the TIM–IPP and the TIM–PGH structures with other liganded and unliganded structures also highlights the conformational flexibility of the ligand and the active site, as well as the conserved mode of ligand binding.