Molecular Tweezers Modulate 14-3-3 Protein-protein Interactions

Overview

Journal Nat Chem

Specialty Chemistry

Date 2013 Feb 21

PMID 23422566

Citations 64

Authors

David Bier

Rolf Rose

Kenny Bravo-Rodriguez

Maria Bartel

Juan Manuel Ramirez-Anguita

Som Dutt

Constanze Wilch

Frank-Gerrit Klarner

Elsa Sanchez-Garcia

Thomas Schrader

Christian Ottmann

Affiliations

Soon will be listed here.

Abstract

Supramolecular chemistry has recently emerged as a promising way to modulate protein functions, but devising molecules that will interact with a protein in the desired manner is difficult as many competing interactions exist in a biological environment (with solvents, salts or different sites for the target biomolecule). We now show that lysine-specific molecular tweezers bind to a 14-3-3 adapter protein and modulate its interaction with partner proteins. The tweezers inhibit binding between the 14-3-3 protein and two partner proteins--a phosphorylated (C-Raf) protein and an unphosphorylated one (ExoS)--in a concentration-dependent manner. Protein crystallography shows that this effect arises from the binding of the tweezers to a single surface-exposed lysine (Lys214) of the 14-3-3 protein in the proximity of its central channel, which normally binds the partner proteins. A combination of structural analysis and computer simulations provides rules for the tweezers' binding preferences, thus allowing us to predict their influence on this type of protein-protein interactions.

Citing Articles

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References

Wang B, Yang H, Liu Y, Jelinek T, Zhang L, Ruoslahti E . Isolation of high-affinity peptide antagonists of 14-3-3 proteins by phage display. Biochemistry. 1999; 38(38):12499-504. DOI: 10.1021/bi991353h. View

Talbiersky P, Bastkowski F, Klarner F, Schrader T . Molecular clip and tweezer introduce new mechanisms of enzyme inhibition. J Am Chem Soc. 2008; 130(30):9824-8. DOI: 10.1021/ja801441j. View

Wells J, McClendon C . Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature. 2007; 450(7172):1001-9. DOI: 10.1038/nature06526. View

Grimme S . Semiempirical GGA-type density functional constructed with a long-range dispersion correction. J Comput Chem. 2006; 27(15):1787-99. DOI: 10.1002/jcc.20495. View

Vassilev A, Kaneko K, Shu H, Zhao Y, DePamphilis M . TEAD/TEF transcription factors utilize the activation domain of YAP65, a Src/Yes-associated protein localized in the cytoplasm. Genes Dev. 2001; 15(10):1229-41. PMC: 313800. DOI: 10.1101/gad.888601. View

Ader C, Schneider R, Hornig S, Velisetty P, Wilson E, Lange A . A structural link between inactivation and block of a K+ channel. Nat Struct Mol Biol. 2008; 15(6):605-12. DOI: 10.1038/nsmb.1430. View

Hermeking H . The 14-3-3 cancer connection. Nat Rev Cancer. 2004; 3(12):931-43. DOI: 10.1038/nrc1230. View

Molzan M, Schumacher B, Ottmann C, Baljuls A, Polzien L, Weyand M . Impaired binding of 14-3-3 to C-RAF in Noonan syndrome suggests new approaches in diseases with increased Ras signaling. Mol Cell Biol. 2010; 30(19):4698-711. PMC: 2950525. DOI: 10.1128/MCB.01636-09. View

Andrews R, Du X, Berndt M . The 14-3-3zeta-GPIb-IX-V complex as an antiplatelet target. Drug News Perspect. 2007; 20(5):285-92. DOI: 10.1358/dnp.2007.20.5.1120215. View

10.

Rose R, Erdmann S, Bovens S, Wolf A, Rose M, Hennig S . Identification and structure of small-molecule stabilizers of 14-3-3 protein-protein interactions. Angew Chem Int Ed Engl. 2010; 49(24):4129-32. DOI: 10.1002/anie.200907203. View

11.

Fantl W, Muslin A, Kikuchi A, Martin J, MacNICOL A, Gross R . Activation of Raf-1 by 14-3-3 proteins. Nature. 1994; 371(6498):612-4. DOI: 10.1038/371612a0. View

12.

Gordo S, Martos V, Santos E, Menendez M, Bo C, Giralt E . Stability and structural recovery of the tetramerization domain of p53-R337H mutant induced by a designed templating ligand. Proc Natl Acad Sci U S A. 2008; 105(43):16426-31. PMC: 2575436. DOI: 10.1073/pnas.0805658105. View

13.

Humphrey W, Dalke A, Schulten K . VMD: visual molecular dynamics. J Mol Graph. 1996; 14(1):33-8, 27-8. DOI: 10.1016/0263-7855(96)00018-5. View

14.

MacKerell Jr A, Feig M, Brooks 3rd C . Extending the treatment of backbone energetics in protein force fields: limitations of gas-phase quantum mechanics in reproducing protein conformational distributions in molecular dynamics simulations. J Comput Chem. 2004; 25(11):1400-15. DOI: 10.1002/jcc.20065. View

15.

Gradl S, Felix J, Isacoff E, Garcia M, Trauner D . Protein surface recognition by rational design: nanomolar ligands for potassium channels. J Am Chem Soc. 2003; 125(42):12668-9. PMC: 1458372. DOI: 10.1021/ja036155z. View

16.

Martos V, Bell S, Santos E, Isacoff E, Trauner D, de Mendoza J . Molecular recognition and self-assembly special feature: Calix[4]arene-based conical-shaped ligands for voltage-dependent potassium channels. Proc Natl Acad Sci U S A. 2009; 106(26):10482-6. PMC: 2705557. DOI: 10.1073/pnas.0813396106. View

17.

Fu H, Coburn J, Collier R . The eukaryotic host factor that activates exoenzyme S of Pseudomonas aeruginosa is a member of the 14-3-3 protein family. Proc Natl Acad Sci U S A. 1993; 90(6):2320-4. PMC: 46078. DOI: 10.1073/pnas.90.6.2320. View

18.

Schumacher B, Skwarczynska M, Rose R, Ottmann C . Structure of a 14-3-3σ-YAP phosphopeptide complex at 1.15 A resolution. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2010; 66(Pt 9):978-84. PMC: 2935210. DOI: 10.1107/S1744309110025479. View

19.

Corradi V, Mancini M, Manetti F, Petta S, Santucci M, Botta M . Identification of the first non-peptidic small molecule inhibitor of the c-Abl/14-3-3 protein-protein interactions able to drive sensitive and Imatinib-resistant leukemia cells to apoptosis. Bioorg Med Chem Lett. 2010; 20(20):6133-7. DOI: 10.1016/j.bmcl.2010.08.019. View

20.

Phillips J, Braun R, Wang W, Gumbart J, Tajkhorshid E, Villa E . Scalable molecular dynamics with NAMD. J Comput Chem. 2005; 26(16):1781-802. PMC: 2486339. DOI: 10.1002/jcc.20289. View