8DBB
Crystal structure of DDT with the selective inhibitor 2,5-Pyridinedicarboxylic Acid
Summary for 8DBB
| Entry DOI | 10.2210/pdb8dbb/pdb |
| Descriptor | D-dopachrome decarboxylase, pyridine-2,5-dicarboxylic acid, CITRIC ACID, ... (4 entities in total) |
| Functional Keywords | trimeric, inhibitor, complex, enzyme, lyase-inhibitor complex, lyase/inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 3 |
| Total formula weight | 38867.65 |
| Authors | Parkins, A.,Banumathi, S.,Pantouris, G. (deposition date: 2022-06-14, release date: 2023-03-08, Last modification date: 2023-10-25) |
| Primary citation | Parkins, A.,Das, P.,Prahaladan, V.,Rangel, V.M.,Xue, L.,Sankaran, B.,Bhandari, V.,Pantouris, G. 2,5-Pyridinedicarboxylic acid is a bioactive and highly selective inhibitor of D-dopachrome tautomerase. Structure, 31:355-, 2023 Cited by PubMed Abstract: Macrophage migration inhibitory factor (MIF) and D-dopachrome tautomerase (D-DT) are two pleotropic cytokines, which are coexpressed in various cell types to activate the cell surface receptor CD74. Via the MIF/CD74 and D-DT/CD74 axes, the two proteins exhibit either beneficial or deleterious effect on human diseases. In this study, we report the identification of 2,5-pyridinedicarboxylic acid (a.k.a. 1) that effectively blocks the D-DT-induced activation of CD74 and demonstrates an impressive 79-fold selectivity for D-DT over MIF. Crystallographic characterization of D-DT-1 elucidates the binding features of 1 and reveals previously unrecognized differences between the MIF and D-DT active sites that explain the ligand's functional selectivity. The commercial availability, low cost, and high selectivity make 1 the ideal tool for studying the pathophysiological functionality of D-DT in disease models. At the same time, our comprehensive biochemical, computational, and crystallographic analyses serve as a guide for generating highly potent and selective D-DT inhibitors. PubMed: 36805127DOI: 10.1016/j.str.2023.01.008 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.3 Å) |
Structure validation
Download full validation report
