Related Experiment Video
Updated: May 19, 2026
Using High Content Imaging to Quantify Target Engagement in Adherent Cells
Published on: November 29, 2018
X-ray structure of p38α bound to TAK-715: comparison with three classic inhibitors
Rita Azevedo1, Mario van Zeeland, Hans Raaijmakers
1Merck Research Laboratories, MSD, PO Box 20, 5340 BH Oss, The Netherlands.
Abstract:
The p38α mitogen-activated protein kinase regulates the synthesis of pro-inflammatory cytokines in response to stimulation by a diverse set of stress signals. Various different chemotypes and clinical candidates that inhibit p38α function have been reported over the years. In this publication, the novel structure of p38α cocrystallized with the clinical candidate TAK-715 is reported. Owing to the impact of crystallization conditions on the conformation of protein kinases (and in particular p38α), the structures of complexes of p38α with SB-203580, SCIO-469 and VX-745 have also been determined to enable in-depth comparison of ligand-induced protein conformations. The impact of experimental conditions on p38α-inhibitor complex structures, most importantly soaking versus cocrystallization, is discussed. Analysis of the structures and quantification of the protein-ligand interactions couples ligand-induced protein conformations to the number of interactions and to inhibitor selectivity against the human kinome. This shows that for the design of novel kinase inhibitors, selectivity is best obtained through maximization of the number of interactions throughout the ATP pocket and the exploitation of specific features in the active site.
Insights
p38α kinase inhibitors, like TAK-715, were studied using novel crystallography. Understanding ligand-induced conformations and interactions is key for designing selective kinase inhibitors.
Area of Science:
- Biochemistry
- Structural Biology
- Pharmacology
Background:
- p38α mitogen-activated protein kinase (MAPK) is crucial for pro-inflammatory cytokine synthesis.
- Numerous p38α inhibitors have been developed, but structural insights into their mechanisms are vital.
Purpose of the Study:
- To report the novel crystal structure of p38α complexed with the clinical candidate TAK-715.
- To compare ligand-induced protein conformations by determining structures with other inhibitors (SB-203580, SCIO-469, VX-745).
- To analyze the impact of experimental conditions on p38α-inhibitor complex structures.
Main Methods:
- X-ray crystallography was used to determine the structures of p38α in complex with various inhibitors.
- Soaking and co-crystallization methods were employed and compared.
- Quantitative analysis of protein-ligand interactions was performed.
Main Results:
- A novel crystal structure of p38α with TAK-715 was determined.
- Ligand-induced conformational changes in p38α were observed and compared across different inhibitors.
- The study quantified protein-ligand interactions and their correlation with inhibitor selectivity.
Conclusions:
- Crystallization conditions significantly influence p38α conformation and inhibitor binding.
- Maximizing interactions within the ATP pocket and exploiting active site features are crucial for designing selective kinase inhibitors.
- Structural insights guide the development of novel p38α inhibitors with improved selectivity.
