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Calorimetric and structural studies of 1,2,3-trisubstituted cyclopropanes as conformationally constrained peptide inhibitors of Src SH2 domain binding.

Davidson JP, Lubman O, Rose T, Waksman G, Martin SF
J Am Chem Soc 124 205-15 (2002)
Cited: 37 times
EuropePMC logo PMID: 11782172

Abstract

Isothermal titration calorimetry and X-ray crystallography have been used to determine the structural and thermodynamic consequences associated with constraining the pTyr residue of the pYEEI ligand for the Src Homology 2 domain of the Src kinase (Src SH2 domain). The conformationally constrained peptide mimics that were used are cyclopropane-derived isosteres whereby a cyclopropane ring substitutes to the N-Calpha-Cbeta atoms of the phosphotyrosine. Comparison of the thermodynamic data for the binding of the conformationally constrained peptide mimics relative to their equivalent flexible analogues as well as a native tetrapeptide revealed an entropic advantage of 5-9 cal mol(-1) K(-1) for the binding of the conformationally constrained ligands. However, an unexpected drop in enthalpy for the binding of the conformationally constrained ligands relative to their flexible analogues was also observed. To evaluate whether these differences reflected conformational variations in peptide binding modes, we have determined the crystal structure of a complex of the Src SH2 domain bound to one of the conformationally constrained peptide mimics. Comparison of this new structure with that of the Src SH2 domain bound to a natural 11-mer peptide (Waksman et al. Cell 1993, 72, 779-790) revealed only very small differences. Hence, cyclopropane-derived peptides are excellent mimics of the bound state of their flexible analogues. However, a rigorous analysis of the structures and of the surface areas at the binding interface, and subsequent computational derivation of the energetic binding parameters, failed to predict the observed differences between the binding thermodynamics of the rigidified and flexible ligands, suggesting that the drop in enthalpy observed with the conformationally constrained peptide mimic arises from sources other than changes in buried surface areas, though the exact origin of the differences remains unclear.

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  2. Binding modes of peptidomimetics designed to inhibit STAT3. Dhanik A, McMurray JS, Kavraki LE. PLoS One 7 e51603 (2012)
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  6. BANΔIT: B'-Factor Analysis for Drug Design and Structural Biology. Barthels F, Schirmeister T, Kersten C. Mol Inform 40 e2000144 (2021)
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  2. Correlating structure and energetics in protein-ligand interactions: paradigms and paradoxes. Martin SF, Clements JH. Annu Rev Biochem 82 267-293 (2013)
  3. A survey of the year 2002 literature on applications of isothermal titration calorimetry. Cliff MJ, Ladbury JE. J Mol Recognit 16 383-391 (2003)
  4. Forces Driving a Magic Bullet to Its Target: Revisiting the Role of Thermodynamics in Drug Design, Development, and Optimization. Minetti CA, Remeta DP. Life (Basel) 12 1438 (2022)

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  3. Conformational constraint in protein ligand design and the inconsistency of binding entropy. Udugamasooriya DG, Spaller MR. Biopolymers 89 653-667 (2008)
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  17. Conformational determinants of phosphotyrosine peptides complexed with the Src SH2 domain. Nachman J, Gish G, Virag C, Pawson T, Pomès R, Pai E. PLoS One 5 e11215 (2010)
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  19. Intramolecular H-bonds govern the recognition of a flexible peptide by an antibody. Miyanabe K, Akiba H, Kuroda D, Nakakido M, Kusano-Arai O, Iwanari H, Hamakubo T, Caaveiro JMM, Tsumoto K. J Biochem 164 65-76 (2018)
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  23. Synthesis and evaluation of phosphopeptides containing iminodiacetate groups as binding ligands of the Src SH2 domain. Ye G, Schuler AD, Ahmadibeni Y, Morgan JR, Faruqui A, Huang K, Sun G, Zebala JA, Parang K. Bioorg Chem 37 133-142 (2009)
  24. Flexibility vs rigidity of amphipathic peptide conjugates when interacting with lipid bilayers. Babii O, Afonin S, Schober T, Komarov IV, Ulrich AS. Biochim Biophys Acta Biomembr 1859 2505-2515 (2017)
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  26. Rapid synthesis of cyclopropane-dipeptide analogues. McMath A, Guillaume D. Nat Prod Res 19 639-643 (2005)


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