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Ras-GAP_WT_Kumon_20190819.pdf (6.44 MB)

Protein Flexibility Catalyzes a Cell Signaling Reaction of the Ras-GAP Complex

submitted on 19.08.2019, 15:43 and posted on 20.08.2019, 16:19 by Keiei Kumon, Masahiro Higashi, Shinji Saito, Shigehiko Hayashi
Many enzyme molecules exhibit characteristic global and slow dynamics which furnish them with allostery realizing remarkable molecular functionalities more than simple chemical catalysis. However, molecular mechanism of a catalytic reaction associated with the molecular flexibility of enzymes is not well-understood. Here we report a hybrid molecular simulation study on GTPase activity of a Ras-GAP protein complex for cell signaling termination. We unveiled that extensive conformational changes of the protein complex and exclusion of internal water molecules are induced upon the transition state (TS) formation in the catalytic reaction and significantly lower the reaction activation free energy. We also revealed that tumor-related mutations perturb those conformational changes upon the TS formation, leading to reduction of the catalytic activity. The findings of the remarkably dynamic protein conformation directly linking to the catalytic reaction have broad implications for understanding of enzyme mechanism and for developments of allosteric drugs and novel catalysts.


JSPS KAKENHI (JP25104004, JP16H04776, JP18H05161)

MEXT program ("Priority Issue on Post-K computer” (Building Innovative Drug Discovery Infrastructure Through Functional 15 16 Control of Biomolecular Systems)


Email Address of Submitting Author


Kyoto University



ORCID For Submitting Author


Declaration of Conflict of Interest

The authors declare no competing financial interests.

Version Notes

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