Molecular docking and spatial coarse graining simulations as tools to investigate substrate recognition, enhancer binding and conformational transitions in indoleamine-2,3-dioxygenase (IDO)

Comparative analysis of rigidity across protein families

“…FIRST/FRODA has been used to examine the inherent mobility of a protein crystal structure for comparison to NMR ensembles [5], to examine possible mechanisms for the assembly of a protein complex [6], to fit the structure of the bacterial chaperonin GroEL to low-resolution cryo-EM data [7], and to examine the relation between protein flexibility and function in enzymes such as IDO [8] and myosin [9]. The coarsegraining provided by the rigidity analysis dramatically reduces the computational cost of simulating flexible motion while retaining all-atom steric detail, making geometric simulation a promising complement to other methods such as molecular dynamics (MD).…”

“…If the RCD of a protein is robust to small structural variations, this justifies the use of rigidity-based coarse graining for simulations of conformational change between structures [7] and structural variation due to flexible motion [5,8,9]. However, if small changes in the structure cause dramatic changes to RCDs, then the RCD of one structure may not be representative.…”

Exploring allosteric activation of LigAB from Sphingobium sp. strain SYK-6 through kinetics, mutagenesis and computational studies

“…In human indoleamine dioxygenase (IDO), activity (V max ) is enhanced through binding of synthetic indole derivatives to an auxiliary binding pocket near the active site, leading to a 35-60% rate enhancement (depending upon the pH and effector molecule) [60][61][62][63][64]. Those studies suggested the existence of an auxiliary binding site for IDO allosteric effectors which was recently identified by computational docking studies using the IDO crystal structure [65]. While these two examples of activation of dioxygenases are both for mammalian enzymes, allosteric activation of non-dioxygenase bacterial enzymes has been previously reported in the literature, as exemplified by the E. coli fructose-1,6-bisphosphatase which is subject to FFA by phosphoenolpyruvate [66].…”

“…Identification of a putative allosteric binding site in LigAB. In order to determine a potential vanillin binding site, computational docking of vanillin onto the C (alpha) and D (beta) chains of the LigAB crystal structure (PDB 1B4U) was performed using a shotgun approach similar to that used to determine the indoleamine derivative allosteric binding site for IDO as mentioned earlier [65]. The docked conformations, from a search centered near the active site, identified several potential binding sites; however, one binding pocket located near the entrance to the active site was occupied by 67% of all conformations generated by AD4 calculations (Fig.…”

Binding Properties of Different Categories of Ido1 Inhibitors: A Microscale Thermophoresis Study

“…Substrate inhibition at high concentrations of L-Trp (1) has been reported as potentially interfering with enzymatic assays aimed at investigating IDO1 inhibition kinetics of small molecules [23]. This observation was formerly explained by the presence of an accessory-binding site into IDO1 structure that may also host small-molecule enhancers of the catalytic activity [24][25][26][27]. However, more recent studies have demonstrated that substrate inhibition by L-Trp (1) is likely due to competition with oxygen in binding to heme cofactor [28,29].…”