Cyclic peptide inhibitors stabilize Gq/11 heterotrimers

Muehle, J.; Rodrigues, M. J.; Alenfelder, J.; Juergenliemke, L.; Guixa-Gonzalez, R.; Bacchin, A.; Andres, F.; Hennig, M.; Schihada, H.; Cruesemann, M.; Koenig, G.; Kostenis, E.; Schertler, G.; Deupi, X.

doi:10.1101/2023.10.24.563737

bioRxiv · 10.1101/2023.10.24.563737

Cyclic peptide inhibitors stabilize Gq/11 heterotrimers

Muehle, J.·Rodrigues, M. J.·Alenfelder, J.·Juergenliemke, L.·Guixa-Gonzalez, R.·Bacchin, A.·Andres, F.·Hennig, M.·Schihada, H.·Cruesemann, M.·Koenig, G.·Kostenis, E.·Schertler, G.·Deupi, X.

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Abstract

Heterotrimeric G proteins play a central role in cellular signaling, acting as switchable molecular regulators. Consequently, pharmacological agents to control G protein activity are of utmost importance to advance our understanding of this signal transduction system. The natural depsipeptides FR900359 (FR) and YM-254890 (YM) are two highly specific and widely used inhibitors of heterotrimeric Gq/11 proteins. These compounds have traditionally been understood to inhibit GDP dissociation by preventing the separation of the GTPase and -helical domains of the G subunit. In this work, we have determined the high-resolution crystal structures of FR and YM bound to heterotrimeric G11 and used them to explain the molecular basis underlying their efficient suppression of G protein signaling. Notably, our data show that FR and YM also function as stabilizers of the interface between the G and G{beta} subunits, acting as molecular adhesives that stabilize the entire heterotrimer. Our results reveal unrecognized mechanistic features that explain how FR and YM effectively blunt Gq/11 signaling in living cells.

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Muehle, J., Rodrigues, M. J., Alenfelder, J., Juergenliemke, L., Guixa-Gonzalez, R., Bacchin, A., Andres, F., Hennig, M., Schihada, H., Cruesemann, M., Koenig, G., Kostenis, E., Schertler, G., Deupi, X.. 2023-10-24. Cyclic peptide inhibitors stabilize Gq/11 heterotrimers. https://doi.org/10.1101/2023.10.24.563737

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