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

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

doi:10.1016/j.str.2023.01.008

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

Journal Article · Wed Mar 01 00:00:00 EST 2023 · Structure

DOI:https://doi.org/10.1016/j.str.2023.01.008· OSTI ID:2318589

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

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. Further, at the same time, our comprehensive biochemical, computational, and crystallographic analyses serve as a guide for generating highly potent and selective D-DT inhibitors.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institute of General Medical Sciences (NIGMS); National Science Foundation (NSF)

Grant/Contract Number:: AC02-05CH11231; P30 GM124169; MRI-1828179

OSTI ID:: 2318589

Alternate ID(s):: OSTI ID: 1968921; OSTI ID: 2323902

Journal Information:: Structure, Journal Name: Structure Vol. 31 Journal Issue: 3; ISSN 0969-2126

Publisher:: ElsevierCopyright Statement

Country of Publication:: United Kingdom

Language:: English

References (62)

4‐Iodopyrimidine Labeling Reveals Nuclear Translocation and Nuclease Activity for Both MIF and MIF2** Xiao, Zhangping; Chen, Deng; Mulder, Fabian Chemistry – A European Journal, Vol. 28, Issue 1 https://doi.org/10.1002/chem.202103030	journal	November 2021
D-dopachrome tautomerase is over-expressed in pancreatic ductal adenocarcinoma and acts cooperatively with macrophage migration inhibitory factor to promote cancer growth Guo, Dawei; Guo, Jinshuai; Yao, Junchao International Journal of Cancer, Vol. 139, Issue 9 https://doi.org/10.1002/ijc.30278	journal	July 2016
Analysis of serum macrophage migration inhibitory factor and D‐dopachrome tautomerase in systemic sclerosis Vincent, Fabien B.; Lin, Emily; Sahhar, Joanne Clinical & Translational Immunology, Vol. 7, Issue 12 https://doi.org/10.1002/cti2.1042	journal	January 2018
Overview of the CCP 4 suite and current developments Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D. Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444910045749	journal	March 2011
Thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione Derivative Inhibits d-Dopachrome Tautomerase Activity and Suppresses the Proliferation of Non-Small Cell Lung Cancer Cells Xiao, Zhangping; Osipyan, Angelina; Song, Shanshan Journal of Medicinal Chemistry, Vol. 65, Issue 3 https://doi.org/10.1021/acs.jmedchem.1c01598	journal	January 2022
Is There a Clinical Future for IDO1 Inhibitors After the Failure of Epacadostat in Melanoma? Van den Eynde, Benoit J.; van Baren, Nicolas; Baurain, Jean-François Annual Review of Cancer Biology, Vol. 4, Issue 1 https://doi.org/10.1146/annurev-cancerbio-030419-033635	journal	March 2020
Selective Targeting of a Disease-Related Conformational Isoform of Macrophage Migration Inhibitory Factor Ameliorates Inflammatory Conditions Thiele, Michael; Kerschbaumer, Randolf J.; Tam, Frederick W. K. The Journal of Immunology, Vol. 195, Issue 5 https://doi.org/10.4049/jimmunol.1500572	journal	September 2015
Oxidized macrophage migration inhibitory factor is a potential new tissue marker and drug target in cancer Schinagl, Alexander; Thiele, Michael; Douillard, Patrice Oncotarget, Vol. 7, Issue 45 https://doi.org/10.18632/oncotarget.11970	journal	September 2016
GROMACS: Fast, flexible, and free Van Der Spoel, David; Lindahl, Erik; Hess, Berk Journal of Computational Chemistry, Vol. 26, Issue 16 https://doi.org/10.1002/jcc.20291	journal	January 2005
MIF interacts with CXCR7 to promote receptor internalization, ERK1/2 and ZAP‐70 signaling, and lymphocyte chemotaxis Alampour‐Rajabi, Setareh; El Bounkari, Omar; Rot, Antal The FASEB Journal, Vol. 29, Issue 11 https://doi.org/10.1096/fj.15-273904	journal	July 2015
D-dopachrome tautomerase contributes to lung epithelial repair via atypical chemokine receptor 3-dependent Akt signaling Song, Shanshan; Liu, Bin; Habibie, Habibie EBioMedicine, Vol. 68 https://doi.org/10.1016/j.ebiom.2021.103412	journal	June 2021
Structural and Kinetic Analyses of Macrophage Migration Inhibitory Factor Active Site Interactions Crichlow, Gregg V.; Lubetsky, Jodi B.; Leng, Lin Biochemistry, Vol. 48, Issue 1 https://doi.org/10.1021/bi8014423	journal	December 2008
MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment Bernhagen, Jürgen; Krohn, Regina; Lue, Hongqi Nature Medicine, Vol. 13, Issue 5 https://doi.org/10.1038/nm1567	journal	April 2007
Structure of a trimeric domain of the MHC class II-associated chaperonin and targeting protein Ii Jasanoff, Alan; Wagner, Gerhard; Wiley, Don C. The EMBO Journal, Vol. 17, Issue 23 https://doi.org/10.1093/emboj/17.23.6812	journal	December 1998
D‐dopachrome tautomerase in cardiovascular and inflammatory diseases—A new kid on the block or just another MIF ? Zan, Chunfang; Yang, Bishan; Brandhofer, Markus The FASEB Journal, Vol. 36, Issue 11 https://doi.org/10.1096/fj.202201213R	journal	October 2022
How good are my data and what is the resolution? Evans, Philip R.; Murshudov, Garib N. Acta Crystallographica Section D Biological Crystallography, Vol. 69, Issue 7 https://doi.org/10.1107/S0907444913000061	journal	June 2013
GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers Abraham, Mark James; Murtola, Teemu; Schulz, Roland SoftwareX, Vol. 1-2 https://doi.org/10.1016/j.softx.2015.06.001	journal	September 2015
MIF but not MIF-2 recruits inflammatory macrophages in an experimental polymicrobial sepsis model Tilstam, Pathricia Veronica; Schulte, Wibke; Holowka, Thomas Journal of Clinical Investigation, Vol. 131, Issue 23 https://doi.org/10.1172/JCI127171	journal	December 2021
Differential regulation of macrophage activation by the MIF cytokine superfamily members MIF and MIF‐2 in adipose tissue during endotoxemia Kim, Bong‐Sung; Tilstam, Pathricia V.; Arnke, Kevin The FASEB Journal, Vol. 34, Issue 3 https://doi.org/10.1096/fj.201901511R	journal	January 2020
CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields Vanommeslaeghe, K.; Hatcher, E.; Acharya, C. Journal of Computational Chemistry https://doi.org/10.1002/jcc.21367	journal	January 2009
A nuclease that mediates cell death induced by DNA damage and poly(ADP-ribose) polymerase-1 Wang, Y.; An, R.; Umanah, G. K. Science, Vol. 354, Issue 6308 https://doi.org/10.1126/science.aad6872	journal	October 2016
Redox-dependent structure and dynamics of macrophage migration inhibitory factor reveal sites of latent allostery Skeens, Erin; Gadzuk-Shea, Meagan; Shah, Dilip Structure, Vol. 30, Issue 6 https://doi.org/10.1016/j.str.2022.03.007	journal	June 2022
Structural Plasticity in the C-Terminal Region of Macrophage Migration Inhibitory Factor-2 Is Associated with an Induced Fit Mechanism for a Selective Inhibitor Pantouris, Georgios; Bucala, Richard; Lolis, Elias J. Biochemistry, Vol. 57, Issue 26 https://doi.org/10.1021/acs.biochem.8b00344	journal	May 2018
An Analysis of MIF Structural Features that Control Functional Activation of CD74 Pantouris, Georgios; Syed, Mansoor Ali; Fan, Chengpeng Chemistry & Biology, Vol. 22, Issue 9 https://doi.org/10.1016/j.chembiol.2015.08.006	journal	September 2015
Allosteric inhibition of macrophage migration inhibitory factor revealed by ibudilast Cho, Y.; Crichlow, G. V.; Vermeire, J. J. Proceedings of the National Academy of Sciences, Vol. 107, Issue 25 https://doi.org/10.1073/pnas.1002716107	journal	June 2010
XDS Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2 https://doi.org/10.1107/S0907444909047337	journal	January 2010
CD44 Is the Signaling Component of the Macrophage Migration Inhibitory Factor-CD74 Receptor Complex Shi, Xuerong; Leng, Lin; Wang, Tian Immunity, Vol. 25, Issue 4 https://doi.org/10.1016/j.immuni.2006.08.020	journal	October 2006
Structural basis for decreased induction of class IB PI3-kinases expression by MIF inhibitors Singh, Abhay Kumar; Pantouris, Georgios; Borosch, Sebastian Journal of Cellular and Molecular Medicine, Vol. 21, Issue 1 https://doi.org/10.1111/jcmm.12949	journal	September 2016
Generalized correlation for biomolecular dynamics Lange, Oliver F.; Grubmüller, Helmut Proteins: Structure, Function, and Bioinformatics, Vol. 62, Issue 4 https://doi.org/10.1002/prot.20784	journal	December 2005
CHARMM36m: an improved force field for folded and intrinsically disordered proteins Huang, Jing; Rauscher, Sarah; Nawrocki, Grzegorz Nature Methods, Vol. 14, Issue 1 https://doi.org/10.1038/nmeth.4067	journal	November 2016
Crystal structure at 2.6-A resolution of human macrophage migration inhibitory factor. Sun, H. W.; Bernhagen, J.; Bucala, R. Proceedings of the National Academy of Sciences, Vol. 93, Issue 11 https://doi.org/10.1073/pnas.93.11.5191	journal	May 1996
MolGpka: A Web Server for Small Molecule pK_a Prediction Using a Graph-Convolutional Neural Network Pan, Xiaolin; Wang, Hao; Li, Cuiyu Journal of Chemical Information and Modeling, Vol. 61, Issue 7 https://doi.org/10.1021/acs.jcim.1c00075	journal	July 2021
Regulation of MIF Enzymatic Activity by an Allosteric Site at the Central Solvent Channel Pantouris, Georgios; Khurana, Leepakshi; Ma, Anthony Cell Chemical Biology, Vol. 27, Issue 6 https://doi.org/10.1016/j.chembiol.2020.05.001	journal	June 2020
The vestigial enzyme D-dopachrome tautomerase protects the heart against ischemic injury Qi, Dake; Atsina, Kwame; Qu, Lintao Journal of Clinical Investigation, Vol. 124, Issue 8 https://doi.org/10.1172/JCI73061	journal	July 2014
D-dopachrome tautomerase (D-DT or MIF-2): Doubling the MIF cytokine family Merk, Melanie; Mitchell, Robert A.; Endres, Stefan Cytokine, Vol. 59, Issue 1 https://doi.org/10.1016/j.cyto.2012.03.014	journal	July 2012
Nanosecond Dynamics Regulate the MIF‐Induced Activity of CD74 Pantouris, Georgios; Ho, Junming; Shah, Dilip Angewandte Chemie International Edition, Vol. 57, Issue 24 https://doi.org/10.1002/anie.201803191	journal	May 2018
Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/S0907444904019158	journal	November 2004
MIF Signal Transduction Initiated by Binding to CD74 Leng, Lin; Metz, Christine N.; Fang, Yan The Journal of Experimental Medicine, Vol. 197, Issue 11 https://doi.org/10.1084/jem.20030286	journal	June 2003
Macrophage CD74 contributes to MIF-induced pulmonary inflammation Takahashi, Koichiro; Koga, Kiyokazu; Linge, Helena M. Respiratory Research, Vol. 10, Issue 1 https://doi.org/10.1186/1465-9921-10-33	journal	May 2009
A Cysteine Variant at an Allosteric Site Alters MIF Dynamics and Biological Function in Homo- and Heterotrimeric Assemblies Skeens, Erin; Pantouris, Georgios; Shah, Dilip Frontiers in Molecular Biosciences, Vol. 9 https://doi.org/10.3389/fmolb.2022.783669	journal	February 2022
Removal of endotoxin from protein solutions by phase separation using triton X-114 Aida, Yoshitomi; Pabst, Michael J. Journal of Immunological Methods, Vol. 132, Issue 2 https://doi.org/10.1016/0022-1759(90)90029-U	journal	September 1990
REFMAC 5 for the refinement of macromolecular crystal structures Murshudov, Garib N.; Skubák, Pavol; Lebedev, Andrey A. Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444911001314	journal	March 2011
Macrophage migration inhibitory factor: a regulator of innate immunity Calandra, Thierry; Roger, Thierry Nature Reviews Immunology, Vol. 3, Issue 10 https://doi.org/10.1038/nri1200	journal	October 2003
Coumarin and Chromen-4-one Analogues as Tautomerase Inhibitors of Macrophage Migration Inhibitory Factor: Discovery and X-ray Crystallography Orita, Masaya; Yamamoto, Satoshi; Katayama, Naoko Journal of Medicinal Chemistry, Vol. 44, Issue 4 https://doi.org/10.1021/jm000386o	journal	February 2001
The N-terminus of MIF regulates the dynamic profile of residues involved in CD74 activation Parkins, Andrew; Skeens, Erin; McCallum, C. Michael Biophysical Journal, Vol. 120, Issue 18 https://doi.org/10.1016/j.bpj.2021.08.025	journal	September 2021
Macrophage migration inhibitory factor stimulates AMP-activated protein kinase in the ischaemic heart Miller, Edward J.; Li, Ji; Leng, Lin Nature, Vol. 451, Issue 7178 https://doi.org/10.1038/nature06504	journal	January 2008
The D-dopachrome tautomerase (DDT) gene product is a cytokine and functional homolog of macrophage migration inhibitory factor (MIF) Merk, M.; Zierow, S.; Leng, L. Proceedings of the National Academy of Sciences, Vol. 108, Issue 34 https://doi.org/10.1073/pnas.1102941108	journal	August 2011
Molecular Cloning of Humand-Dopachrome Tautomerase cDNA: N-terminal Proline Is Essential for Enzyme Activation Nishihira, Jun; Fujinaga, Mami; Kuriyama, Takeshi Biochemical and Biophysical Research Communications, Vol. 243, Issue 2 https://doi.org/10.1006/bbrc.1998.8123	journal	February 1998
Crystal Structure of Human d-Dopachrome Tautomerase, a Homologue of Macrophage Migration Inhibitory Factor, at 1.54 Å Resolution^, Sugimoto, Hiroshi; Taniguchi, Masae; Nakagawa, Atsushi Biochemistry, Vol. 38, Issue 11 https://doi.org/10.1021/bi982184o	journal	February 1999
Molecular Profile of Peripheral Blood Mononuclear Cells from Patients with Rheumatoid Arthritis Edwards, Christopher J.; Feldman, Jeffrey L.; Beech, Jonathan Molecular Medicine, Vol. 13, Issue 1-2 https://doi.org/10.2119/2006-000056.Edwards	journal	January 2007
Mechanism of a Reaction in Vitro Associated with Delayed-Type Hypersensitivity Bloom, B. R.; Bennett, B. Science, Vol. 153, Issue 3731 https://doi.org/10.1126/science.153.3731.80	journal	July 1966
A functional heteromeric MIF receptor formed by CD74 and CXCR4 Schwartz, Verena; Lue, Hongqi; Kraemer, Sandra FEBS Letters, Vol. 583, Issue 17 https://doi.org/10.1016/j.febslet.2009.07.058	journal	August 2009
The Tautomerase Active Site of Macrophage Migration Inhibitory Factor Is a Potential Target for Discovery of Novel Anti-inflammatory Agents Lubetsky, Jodi B.; Dios, Angeles; Han, Jialian Journal of Biological Chemistry, Vol. 277, Issue 28 https://doi.org/10.1074/jbc.M203220200	journal	July 2002
The Immunoregulatory Mediator Macrophage Migration Inhibitory Factor (MIF) Catalyzes a Tautomerization Reaction Rosengren, Evald; Bucala, Richard; Åman, Pierre Molecular Medicine, Vol. 2, Issue 1 https://doi.org/10.1007/BF03402210	journal	January 1996
MIF as a disease target: ISO-1 as a proof-of-concept therapeutic Al-Abed, Yousef; VanPatten, Sonya Future Medicinal Chemistry, Vol. 3, Issue 1 https://doi.org/10.4155/fmc.10.281	journal	January 2011
A structurally preserved allosteric site in the MIF superfamily affects enzymatic activity and CD74 activation in D-dopachrome tautomerase Chen, Emily; Reiss, Krystle; Shah, Dilip Journal of Biological Chemistry, Vol. 297, Issue 3 https://doi.org/10.1016/j.jbc.2021.101061	journal	September 2021
A Novel MIF Signaling Pathway Drives the Malignant Character of Pancreatic Cancer by Targeting NR3C2 Yang, Shouhui; He, Peijun; Wang, Jian Cancer Research, Vol. 76, Issue 13 https://doi.org/10.1158/0008-5472.CAN-15-2841	journal	June 2016
VMD: Visual molecular dynamics Humphrey, William; Dalke, Andrew; Schulten, Klaus Journal of Molecular Graphics, Vol. 14, Issue 1 https://doi.org/10.1016/0263-7855(96)00018-5	journal	February 1996
Targeting distinct tautomerase sites of D‐DT and MIF with a single molecule for inhibition of neutrophil lung recruitment Rajasekaran, Deepa; Zierow, Swen; Syed, Mansoor The FASEB Journal, Vol. 28, Issue 11 https://doi.org/10.1096/fj.14-256636	journal	July 2014
A functional promoter polymorphism in the macrophage migration inhibitory factor (MIF) gene associated with disease severity in rheumatoid arthritis Baugh, J. A.; Chitnis, S.; Donnelly, S. C. Genes & Immunity, Vol. 3, Issue 3 https://doi.org/10.1038/sj.gene.6363867	journal	May 2002
Interaction of pyridine-2,5-dicarboxylic acid with heavy metal ions in aqueous solutions Norkus, Eugenijus; Gaidamauskas, Ernestas; Stalnionienė, Irena Heteroatom Chemistry, Vol. 16, Issue 4 https://doi.org/10.1002/hc.20123	journal	January 2005
Human indoleamine 2,3-dioxygenase-2 has substrate specificity and inhibition characteristics distinct from those of indoleamine 2,3-dioxygenase-1 Pantouris, Georgios; Serys, Martynas; Yuasa, Hajime J. Amino Acids, Vol. 46, Issue 9 https://doi.org/10.1007/s00726-014-1766-3	journal	May 2014

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60 APPLIED LIFE SCIENCES
D-dopachrome tautomerase
inhibitor
CD74
selectivity
bioactive
active site volume

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

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