6UD5
Crystal structure of human tryptophan 2,3-dioxygenase in complex with carbon monoxide and tryptophan
Summary for 6UD5
| Entry DOI | 10.2210/pdb6ud5/pdb |
| Related | 6UBP |
| Descriptor | Tryptophan 2,3-dioxygenase, PROTOPORPHYRIN IX CONTAINING FE, CARBON MONOXIDE, ... (5 entities in total) |
| Functional Keywords | tryptophan dioxygenase, carbon monoxide, oxidoreductase, tryptophan |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 184941.93 |
| Authors | Pham, K.N.,Lewis-Ballester, A.,Yeh, S.R. (deposition date: 2019-09-18, release date: 2021-02-03, Last modification date: 2023-10-11) |
| Primary citation | Pham, K.N.,Lewis-Ballester, A.,Yeh, S.R. Conformational Plasticity in Human Heme-Based Dioxygenases. J.Am.Chem.Soc., 143:1836-1845, 2021 Cited by PubMed Abstract: Human indoleamine 2,3-dioxygenase 1 (hIDO1) and human tryptophan dioxygenase (hTDO) are two important heme proteins that degrade the essential amino acid, l-tryptophan (Trp), along the kynurenine pathway. The two enzymes share a similar active site structure and an analogous catalytic mechanism, but they exhibit a variety of distinct functional properties. Here we used carbon monoxide (CO) as a structural probe to interrogate how the functionalities of the two enzymes are encoded in their structures. With X-ray crystallography, we detected an unexpected photochemical intermediate trapped in a crystal of the hIDO1-CO-Trp complex, where CO is photolyzed from the heme iron by X-rays at cryogenic temperatures (100 K). The CO photolysis triggers a large-scale migration of the substrate Trp, as well as the photolyzed CO, from the active site to a temporary binding site, Sa*. It is accompanied by a large conformational change to an active site loop, JK-Loop, despite the severely restricted protein motion under the frozen conditions, which highlights the remarkable conformational plasticity of the hIDO1 protein. Comparative studies of a crystal of the hTDO-CO-Trp complex show that CO and Trp remain bound in the active site under comparable X-ray illumination, indicating a much more rigid protein architecture. The data offer important new insights into the structure and function relationships of the heme-based dioxygenases and provide new guidelines for structure-based design of inhibitors targeting them. PubMed: 33373218DOI: 10.1021/jacs.0c09970 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.05 Å) |
Structure validation
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