6PYZ
Crystal Structure of human Tryptophan 2,3-dioxygenase in complex with PF-06840003 in Active Site
Summary for 6PYZ
| Entry DOI | 10.2210/pdb6pyz/pdb |
| Related | 6PYY |
| Descriptor | Tryptophan 2,3-dioxygenase, PROTOPORPHYRIN IX CONTAINING FE, (3S)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione, ... (5 entities in total) |
| Functional Keywords | tryptophan dioxygenase, pf-06840003, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 184997.94 |
| Authors | Pham, K.N.,Lewis-Ballester, A.,Yeh, S.R. (deposition date: 2019-07-31, release date: 2020-01-01, Last modification date: 2023-11-15) |
| Primary citation | Pham, K.N.,Lewis-Ballester, A.,Yeh, S.R. Structural Basis of Inhibitor Selectivity in Human Indoleamine 2,3-Dioxygenase 1 and Tryptophan Dioxygenase. J.Am.Chem.Soc., 141:18771-18779, 2019 Cited by PubMed Abstract: Indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan dioxygenase (hTDO) are two of the only three heme-based dioxygenases in humans. They have recently been identified as key cancer immunotherapeutic drug targets. While structures of hIDO1 in complex with inhibitors have been documented, so far there are no structures of hTDO-inhibitor complexes available. Here we use PF-06840003 (IPD), a hIDO1-selective inhibitor in clinical trials, as a structural probe to elucidate inhibitor-selectivity in hIDO1 versus hTDO. Spectroscopic studies show that IPD exhibits 400-fold higher inhibition activity toward hIDO1 with respect to hTDO. Crystallographic structures reveal that the binding pocket of IPD in the active site in hIDO1 is much more flexible as compared to that in hTDO, which offers a molecular explanation for the superior inhibition activity of IPD in hIDO1 with respect to hTDO. In addition to the IPD bound in the active site, a second IPD molecule was identified in an inhibitory site on the proximal side of the heme in hIDO1 and in an exosite that is ∼40 Å away from the active site in hTDO. Taken together the data provide new insights into structure-based design of mono and dual inhibitors targeting hIDO1 and/or hTDO. PubMed: 31682426DOI: 10.1021/jacs.9b08871 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.02 Å) |
Structure validation
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