6VBN
Crystal Structure of hTDO2 bound to inhibitor GNE1
Summary for 6VBN
| Entry DOI | 10.2210/pdb6vbn/pdb |
| Descriptor | Tryptophan 2,3-dioxygenase, PROTOPORPHYRIN IX CONTAINING FE, 1,5-anhydro-2,3-dideoxy-3-[(5S)-5H-imidazo[5,1-a]isoindol-5-yl]-D-threo-pentitol, ... (4 entities in total) |
| Functional Keywords | tdo, ido, cancer immunotherapy, heme, oxidoreductase, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 185534.04 |
| Authors | Harris, S.F.,Oh, A. (deposition date: 2019-12-19, release date: 2020-05-06, Last modification date: 2023-10-11) |
| Primary citation | Parr, B.T.,Pastor, R.,Sellers, B.D.,Pei, Z.,Jaipuri, F.A.,Castanedo, G.M.,Gazzard, L.,Kumar, S.,Li, X.,Liu, W.,Mendonca, R.,Pavana, R.K.,Potturi, H.,Shao, C.,Velvadapu, V.,Waldo, J.P.,Wu, G.,Yuen, P.W.,Zhang, Z.,Zhang, Y.,Harris, S.F.,Oh, A.J.,DiPasquale, A.,Dement, K.,La, H.,Goon, L.,Gustafson, A.,VanderPorten, E.C.,Mautino, M.R.,Liu, Y. Implementation of the CYP Index for the Design of Selective Tryptophan-2,3-dioxygenase Inhibitors. Acs Med.Chem.Lett., 11:541-549, 2020 Cited by PubMed Abstract: A class of imidazoisoindole (III) heme-binding indoleamine-2,3-dioxygenase (IDO1) inhibitors were optimized via structure-based drug design into a series of tryptophan-2,3-dioxygenase (TDO)-selective inhibitors. Kynurenine pathway modulation was demonstrated , which enabled evaluation of TDO as a potential cancer immunotherapy target. As means of mitigating the risk of drug-drug interactions arising from cytochrome P450 inhibition, a novel property-based drug design parameter, herein referred to as the CYP Index, was implemented for the design of inhibitors with appreciable selectivity for TDO over CYP3A4. We anticipate the CYP Index will be a valuable design parameter for optimizing CYP inhibition of any small molecule inhibitor containing a Lewis basic motif capable of binding heme. PubMed: 32292562DOI: 10.1021/acsmedchemlett.0c00004 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.18 Å) |
Structure validation
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