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Crystal structures of a high-affinity macrocyclic peptide mimetic in complex with the Grb2 SH2 domain.

Phan J, Shi ZD, Burke TR, Waugh DS
J Mol Biol 353 104-15 (2005)
Cited: 13 times
EuropePMC logo PMID: 16165154

Abstract

The high-affinity binding of the growth factor receptor-bound protein 2 (Grb2) SH2 domain to tyrosine-phosphorylated cytosolic domains of receptor tyrosine kinases (RTKs) is an attractive target for therapeutic intervention in many types of cancer. We report here two crystal forms of a complex between the Grb2 SH2 domain and a potent non-phosphorus-containing macrocyclic peptide mimetic that exhibits significant anti-proliferative effects against erbB-2-dependent breast cancers. This agent represents a "second generation" inhibitor with greatly improved binding affinity and bio-availability compared to its open-chain counterpart. The structures were determined at 2.0A and 1.8A with one and two domain-swapped dimers per asymmetric unit, respectively. The mode of binding and specific interactions between the protein and the inhibitor provide insight into the high potency of this class of macrocylic compounds and may aid in further optimization as part of the iterative rational drug design process.

Articles - 2aoa mentioned but not cited (2)

  1. Structural and energetic aspects of Grb2-SH2 domain-swapping. Benfield AP, Whiddon BB, Clements JH, Martin SF. Arch Biochem Biophys 462 47-53 (2007)
  2. Synthesis and structural characterization of a monocarboxylic inhibitor for GRB2 SH2 domain. Xiao T, Sun L, Zhang M, Li Z, Haura EB, Schonbrunn E, Ji H. Bioorg Med Chem Lett 51 128354 (2021)


Reviews citing this publication (2)

  1. Progress towards the development of SH2 domain inhibitors. Kraskouskaya D, Duodu E, Arpin CC, Gunning PT. Chem Soc Rev 42 3337-3370 (2013)
  2. On the relationship between low-frequency normal modes and the large-scale conformational changes of proteins. Mahajan S, Sanejouand YH. Arch Biochem Biophys 567 59-65 (2015)

Articles citing this publication (9)

  1. Macrocycles: lessons from the distant past, recent developments, and future directions. Yudin AK. Chem Sci 6 30-49 (2015)
  2. Anatomy of β-strands at protein-protein interfaces. Watkins AM, Arora PS. ACS Chem Biol 9 1747-1754 (2014)
  3. Structural basis of binding by cyclic nonphosphorylated peptide antagonists of Grb7 implicated in breast cancer progression. Ambaye ND, Pero SC, Gunzburg MJ, Yap M, Clayton DJ, Del Borgo MP, Perlmutter P, Aguilar MI, Shukla GS, Peletskaya E, Cookson MM, Krag DN, Wilce MC, Wilce JA. J Mol Biol 412 397-411 (2011)
  4. Solution structure of the Grb2 SH2 domain complexed with a high-affinity inhibitor. Ogura K, Shiga T, Yokochi M, Yuzawa S, Burke TR, Inagaki F. J Biomol NMR 42 197-207 (2008)
  5. Structural and biophysical investigation of the interaction of a mutant Grb2 SH2 domain (W121G) with its cognate phosphopeptide. Papaioannou D, Geibel S, Kunze MB, Kay CW, Waksman G. Protein Sci 25 627-637 (2016)
  6. Structural and functional properties of Grb2 SH2 dimer in CD28 binding. Hosoe Y, Numoto N, Inaba S, Ogawa S, Morii H, Abe R, Ito N, Oda M. Biophys Physicobiol 16 80-88 (2019)
  7. The reactivity and conformational control of cyclic tetrapeptides derived from aziridine-containing amino acids. Chung BKW, White CJ, Scully CCG, Yudin AK. Chem Sci 7 6662-6668 (2016)
  8. Utilization of achiral alkenyl amines for the preparation of high affinity Grb2 SH2 domain-binding macrocycles by ring-closing metathesis. Liu F, Worthy KM, Bindu L, Giubellino A, Bottaro DP, Fisher RJ, Burke TR. Org Biomol Chem 5 367-372 (2007)
  9. GRB2 dimerization mediated by SH2 domain-swapping is critical for T cell signaling and cytokine production. Sandouk A, Xu Z, Baruah S, Tremblay M, Hopkins JB, Chakravarthy S, Gakhar L, Schnicker NJ, Houtman JCD. Sci Rep 13 3505 (2023)


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