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First comprehensive structural and biophysical analysis of MAPK13 inhibitors targeting DFG-in and DFG-out binding modes

Journal Article · · Biochimica et Biophysica Acta - General Subjects
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  1. Washington Univ. School of Medicine, St. Louis, MO (United States)
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Background: P38 MAP kinases are centrally involved in mediating extracellular signaling in various diseases. While much attention has previously been focused on the ubiquitously expressed family member MAPK14 (p38α), recent studies indicate that family members such as MAPK13 (p38δ) display a more selective cellular and tissue expression and might therefore represent a specific kinase to target in certain diseases. Methods: To facilitate the design of potent and specific inhibitors, we present in this paper the structural, biophysical, and functional characterization of two new MAPK13-inhibitor complexes, as well as the first comprehensive structural, biophysical, and functional analysis of MAPK13 complexes with four different inhibitor compounds of greatly varying potency. Results: These inhibitors display IC50 values either in the nanomolar range or micromolar range (> 800-fold range). The nanomolar inhibitors exhibit much longer ligand-enzyme complex half-lives compared to the micromolar inhibitors as measured by biolayer interferometry. Crystal structures of the MAPK13 inhibitor complexes reveal that the nanomolar inhibitors engage MAPK13 in the DFG-out binding mode, while the micromolar inhibitors are in the DFG-in mode. Detailed structural and computational docking analyses suggest that this difference in binding mode engagement is driven by conformational restraints imposed by the chemical structure of the inhibitors, and may be fortified by an additional hydrogen bond to MAPK13 in the nanomolar inhibitors. Conclusions: These studies provide a structural basis for understanding the differences in potency exhibited by these inhibitors. General significance: They also provide the groundwork for future studies to improve specificity, potency, pharmacodynamics, and pharmacokinetic properties.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS)
Sponsoring Organization:
American Heart Association (AHA); National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER)
Grant/Contract Number:
AC02-05CH11231; AC02-06CH11357
OSTI ID:
1329425
Alternate ID(s):
OSTI ID: 1396466
Journal Information:
Biochimica et Biophysica Acta - General Subjects, Journal Name: Biochimica et Biophysica Acta - General Subjects Journal Issue: 11 Vol. 1860; ISSN 0304-4165
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Chronic inflammatory lung disease
Differential scanning fluorimetry
Inhibitor half-lives
Kinase inhibitor
Structure-based drug design
p38 kinase