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Comment
. 2020 Feb 18;117(7):3365-3367.
doi: 10.1073/pnas.1921236117. Epub 2020 Feb 11.

Reply to Tran et al.: Dimeric KRAS protein-protein interaction stabilizers

Dirk Kessler  1 , Andreas Gollner  1 , Michael Gmachl  1 , Andreas Mantoulidis  1 , Laetitia J Martin  1 , Andreas Zoephel  1 , Moriz Mayer  1 , David Covini  1 , Silke Fischer  1 , Thomas Gerstberger  1 , Teresa Gmaschitz  1 , Craig Goodwin  2 , Peter Greb  1 , Daniela Häring  1 , Wolfgang Hela  1 , Johann Hoffmann  1 , Jale Karolyi-Oezguer  1 , Petr Knesl  1 , Stefan Kornigg  1 , Manfred Koegl  1 , Roland Kousek  1 , Lyne Lamarre  1 , Franziska Moser  3 , Silvia Munico-Martinez  1 , Christoph Peinsipp  1 , Jason Phan  2 , Jörg Rinnenthal  1 , Jiqing Sai  2 , Christian Salamon  1 , Yvonne Scherbantin  1 , Katharina Schipany  1 , Renate Schnitzer  1 , Andreas Schrenk  1 , Bernadette Sharps  1 , Gabriella Siszler  1 , Qi Sun  2 , Alex Waterson  4   5 , Bernhard Wolkerstorfer  1 , Markus Zeeb  3 , Mark Pearson  1 , Stephen W Fesik  2   4   5 , Darryl B McConnell  6
Affiliations
Comment

Reply to Tran et al.: Dimeric KRAS protein-protein interaction stabilizers

Dirk Kessler et al. Proc Natl Acad Sci U S A. .
No abstract available

PubMed Disclaimer

Conflict of interest statement

Competing interest statement: D.K., A.G., M.G., A.M., L.J.M., A.Z., M.M., D.C., S.F., T. Gerstberger, T. Gmaschitz, P.G., D.H., W.H., J.H., J.K.-O., P.K., S.K., M.K., R.K., L.L., F.M., S.M.-M., C.P., J.R., C.S., Y.S., K.S., R.S., A.S., B.S., G.S., B.W., M.Z., M.P., and D.B.M. were employees of Boehringer Ingelheim at the time of the work.

Figures

Fig. 1.
Fig. 1.
KRAS dimers and biophysical validation. (A) KRAS G12D modeled dimer with BI-2852 (Protein Data Bank [PDB] ID code 6GJ8). The dimer interface was generated with symmetry operations from the published structure, showing a β-sandwich interface. (B) Cocrystal structure of KRAS G12D with compound 2 showing a similar β-sandwich interface as with BI-2852. (C) Published dimeric KRAS-G12D apo system (PDB ID code 6QUU) with an extended β-sheet interface. (D) Structure of compound 2 soaked in published KRAS-G12D soaking system. The compound needs to adapt to the extended β-sheet interface. (E) Isothermal titration calorimetry experiments with compound 2 showing binding to KRAS-G12D. (F) 2FoFc density around cocrystallized compound 2 at 1.57-Å resolution showing unambiguous binding. The interacting amino acids of both KRAS monomers are labeled. (G) 2FoFc density around compound 2 soaked in KRAS G12D at 1.9-Å resolution showing unambiguous binding of the ligand. The interacting amino acids of both KRAS monomers are labeled, respectively.
See this image and copyright information in PMC

Comment on

  • Drugging an undruggable pocket on KRAS.
    Kessler D, Gmachl M, Mantoulidis A, Martin LJ, Zoephel A, Mayer M, Gollner A, Covini D, Fischer S, Gerstberger T, Gmaschitz T, Goodwin C, Greb P, Häring D, Hela W, Hoffmann J, Karolyi-Oezguer J, Knesl P, Kornigg S, Koegl M, Kousek R, Lamarre L, Moser F, Munico-Martinez S, Peinsipp C, Phan J, Rinnenthal J, Sai J, Salamon C, Scherbantin Y, Schipany K, Schnitzer R, Schrenk A, Sharps B, Siszler G, Sun Q, Waterson A, Wolkerstorfer B, Zeeb M, Pearson M, Fesik SW, McConnell DB. Kessler D, et al. Proc Natl Acad Sci U S A. 2019 Aug 6;116(32):15823-15829. doi: 10.1073/pnas.1904529116. Epub 2019 Jul 22. Proc Natl Acad Sci U S A. 2019. PMID: 31332011 Free PMC article.
  • The small molecule BI-2852 induces a nonfunctional dimer of KRAS.
    Tran TH, Alexander P, Dharmaiah S, Agamasu C, Nissley DV, McCormick F, Esposito D, Simanshu DK, Stephen AG, Balius TE. Tran TH, et al. Proc Natl Acad Sci U S A. 2020 Feb 18;117(7):3363-3364. doi: 10.1073/pnas.1918164117. Epub 2020 Feb 11. Proc Natl Acad Sci U S A. 2020. PMID: 32047043 Free PMC article. No abstract available.

References

    1. Tran T. H., et al. , The small molecule BI-2852 induces a nonfunctional dimer of KRAS. Proc. Natl. Acad. Sci. U.S.A. 117, 3363–3364 (2020). - PMC - PubMed
    1. Kessler D., et al. , Drugging an undruggable pocket on KRAS. Proc. Natl. Acad. Sci. U.S.A. 116, 15823–15829 (2019). - PMC - PubMed
    1. Bondeson D. P., Crews C. M., Targeted protein degradation by small molecules. Annu. Rev. Pharmacol. Toxicol. 57, 107–123 (2017). - PMC - PubMed
    1. Bergner A., et al. , KRAS binders hidden in nature. Chemistry 25, 12037–12041 (2019). - PMC - PubMed
    1. Jang H., Muratcioglu S., Gursoy A., Keskin O., Nussinov R., Membrane-associated Ras dimers are isoform-specific: K-Ras dimers differ from H-Ras dimers. Biochem. J. 473, 1719–1732 (2016). - PMC - PubMed

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