2,5-Pyridinedicarboxylic acid is a bioactive and highly selective inhibitor of D-dopachrome tautomerase

Andrew Parkins; Pragnya Das; Varsha Prahaladan; Vanessa M Rangel; Liang Xue; Banumathi Sankaran; Vineet Bhandari; Georgios Pantouris

doi:10.1016/j.str.2023.01.008

2,5-Pyridinedicarboxylic acid is a bioactive and highly selective inhibitor of D-dopachrome tautomerase

Structure. 2023 Mar 2;31(3):355-367.e4. doi: 10.1016/j.str.2023.01.008. Epub 2023 Feb 17.

Authors

Andrew Parkins¹, Pragnya Das², Varsha Prahaladan², Vanessa M Rangel¹, Liang Xue¹, Banumathi Sankaran³, Vineet Bhandari², Georgios Pantouris⁴

Affiliations

¹ Department of Chemistry, University of the Pacific, Stockton, CA 95211, USA.
² Division of Neonatology, Department of Pediatrics, The Children's Regional Hospital at Cooper, Camden, NJ 08103, USA.
³ Molecular Biophysics and Integrated Bioimaging, Berkeley Center for Structural Biology, 1 Cyclotron Road, Lawrence Berkeley Nat. Lab, Berkeley, CA 94720, USA.
⁴ Department of Chemistry, University of the Pacific, Stockton, CA 95211, USA. Electronic address: gpantouris@pacific.edu.

PMID: 36805127
DOI: 10.1016/j.str.2023.01.008

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.

Keywords: CD74; D-dopachrome tautomerase; active site volume; bioactive; inhibitor; selectivity.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

MeSH terms

Catalytic Domain*
Humans

Substances

dopachrome isomerase
2,5-Pyridinedicarboxylic acid

Grants and funding

HHMI/Howard Hughes Medical Institute/United States