Skip to main content

Advertisement

SpringerLink
Log in

Making ERRFI1-Derived Peptides ‘Bindable’ to the Allosteric Dimerization Interface of Breast Cancer ERBB3 Kinase by Adding a Nonbonded Interaction System

  • Published:
International Journal of Peptide Research and Therapeutics Aims and scope Submit manuscript

Abstract

The ERBB3 is a member of human receptor tyrosine kinase ErbB family involved in various cellular processes, which has been recognized as a new and promising druggable target of breast cancer and some other gynecological tumors. The ERRFI1 protein is a natural negative regulator of ErbB signaling and has been found to inactivate ERBB3 kinase activity by directly disrupting the kinase dimerization with its ErbB-binding region (EBR). The ERRFI1 EBR domain contains two functional segments 1 and 2 as well as a flexible loop (FL) linker between the two segments, which can only weakly interact with ERBB3 kinase domain to form a reversible, transient encounter complex. Here, we demonstrated that the binding affinity and recognition specificity of ERBB3 interaction with ERRFI1 FL peptides can be improved essentially by just adding a designed nonbonded interaction system across the kinase–peptide complex interface. The nonbonded system consists of one or two hydrogen bonds as well as a double aromatic stacking. High-level theoretical calculations indicated that these nonbonded forces can work together to confer considerable stability and specificity to the complex, thus making ERRFI1-derived peptides ‘bindable’ to ERBB3 kinase domain. The theoretical analysis was further substantiated by calorimetric study, which revealed that the designed nonbonded system can improve the kinase–peptide binding free energy by − 5 to – 20 kJ/mol with different arrangements of its nonbonded forces.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Appert-Collin A, Hubert P, Crémel G, Bennasroune A (2015) Role of ErbB receptors in cancer cell migration and invasion. Front Pharmacol 6:283

    Article  Google Scholar 

  • Ayati A, Moghimi S, Salarinejad S, Safavi M, Pouramiri B, Foroumadi A (2020) A review on progression of epidermal growth factor receptor (EGFR) inhibitors as an efficient approach in cancer targeted therapy. Bioorg Chem 99:103811

    Article  CAS  Google Scholar 

  • Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The protein data bank. Nucl Acids Res 28:235–242

    Article  CAS  Google Scholar 

  • Boys SF, Bernardi F (1970) The calculation of small molecular interactions by the differences of separate total energies. Some procedures with reduced errors. Mol Phys 19:553–566

    Article  CAS  Google Scholar 

  • Gallivan JP, Dougherty DA (1999) Cation-pi interactions in structural biology. Proc Natl Acad Sci USA 96:9459–9464

    Article  CAS  Google Scholar 

  • Gschwind A, Fischer OM, Ullrich A (2004) The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat Rev Cancer 4:361–370

    Article  CAS  Google Scholar 

  • Hsieh AC, Moasser MM (2007) Targeting HER proteins in cancer therapy and the role of the non-target HER3. Br J Cancer 97:453–457

    Article  CAS  Google Scholar 

  • Ko J, Park H, Heo L, Seok C (2012) GalaxyWEB server for protein structure prediction and refinement. Nucl Acids Res 40:W294–W297

    Article  CAS  Google Scholar 

  • Kortemme T, Kim DE, Baker D (2004) Computational alanine scanning of protein-protein interfaces. Sci STKE 2004:pl2.

  • Li C, Wang S, Xing Z, Lin A, Liang K, Song J, Hu Q, Yao J, Chen Z, Park PK, Hawke DH, Zhou J, Zhou Y, Zhang S, Liang H, Hung MC, Gallick GE, Han L, Lin C, Yang L (2017) A ROR1-HER3-lncRNA signalling axis modulates the Hippo-YAP pathway to regulate bone metastasis. Nat Cell Biol 19:106–119

    Article  CAS  Google Scholar 

  • Li Z, Miao Q, Yan F, Meng Y, Zhou P (2019) Machine learning in quantitative protein–peptide affinity prediction: implications for therapeutic peptide design. Curr Drug Metab 20:170–176

    Article  CAS  Google Scholar 

  • Liu H, Dou SF, Zhang X, Wen QL, Mu YN (2016) Rational improvement of peptide affinity to human pregnancy-related serine protease HtrA3 PDZ domain by introducing a halogen bond to the domain–peptide complex interface. Int J Pept Res Ther 22:371–376

    Article  CAS  Google Scholar 

  • Liu X, Liu S, Lyu H, Riker AI, Zhang Y, Liu B (2019) Development of effective therapeutics targeting HER3 for cancer treatment. Biol Proced Online 21:5

    Article  Google Scholar 

  • London N, Raveh B, Cohen E, Fathi G, Schueler-Furman O (2011) Rosetta FlexPepDock web server–high resolution modeling of peptide-protein interactions. Nucl Acids Res 39:W249–W253

    Article  CAS  Google Scholar 

  • Lu J, Li H, Wang Y, Südhof TC, Rizo J (2005) Solution structure of the RIM1alpha PDZ domain in complex with an ELKS1b C-terminal peptide. J Mol Biol 352:455–466

    Article  CAS  Google Scholar 

  • Ma J, Lyu H, Huang J, Liu B (2014) Targeting of erbB3 receptor to overcome resistance in cancer treatment. Mol Cancer 13:105

    Article  Google Scholar 

  • Maruyama IN (2014) Mechanisms of activation of receptor tyrosine kinases: monomers or dimers. Cells 3:304–330

    Article  Google Scholar 

  • Maupetit J, Derreumaux P, Tuffery P (2009) PEP-FOLD: an online resource for de novo peptide structure prediction. Nucl Acids Res 37:W498–W503

    Article  CAS  Google Scholar 

  • Okon M, Moraes TF, Lario PI, Creagh AL, Haynes CA, Strynadka NC, McIntosh LP (2008) Structural characterization of the type-III pilot-secretin complex from Shigella flexneri. Structure 16:1544–1554

    Article  CAS  Google Scholar 

  • Park E, Kim N, Ficarro SB, Zhang Y, Lee BI, Cho A, Kim K, Park AKJ, Park WY, Murray B, Meyerson M, Beroukhim R, Marto JA, Cho J, Eck MJ (2015) Structure and mechanism of activity-based inhibition of the EGF receptor by Mig6. Nat Struct Mol Biol 22:703–711

    Article  CAS  Google Scholar 

  • Qiao Z, Wang S (2021) Directed molecular engineering of Mig6 peptide selectivity between proto-oncogene ErbB family receptor tyrosine kinases. Biotechnol Bioproc Eng 26:277–285

    Article  CAS  Google Scholar 

  • Raveh B, London N, Schueler-Furman O (2010) Sub-angstrom modeling of complexes between flexible peptides and globular proteins. Proteins 78:2029–2040

    Article  CAS  Google Scholar 

  • Sithanandam G, Anderson LM (2008) The ERBB3 receptor in cancer and cancer gene therapy. Cancer Gene Ther 15:413–448

    Article  CAS  Google Scholar 

  • Spiliotopoulos D, Kastritis PL, Melquiond AS, Bonvin AM, Musco G, Rocchia W, Spitaleri A (2016) dMM-PBSA: a new HADDOCK scoring function for protein–peptide docking. Front Mol Biosci 3:46

    Article  Google Scholar 

  • Travis A, Pinder SE, Robertson JF, Bell JA, Wencyk P, Gullick WJ, Nicholson RI, Poller DN, Blamey RW, Elston CW, Ellis IO (1996) C-erbB-3 in human breast carcinoma: expression and relation to prognosis and established prognostic indicators. Br J Cancer 74:229–233

    Article  CAS  Google Scholar 

  • Wang Z, Raines LL, Hooy RM, Roberson H, Leahy DJ, Cole PA (2013) Tyrosine phosphorylation of mig6 reduces its inhibition of the epidermal growth factor receptor. ACS Chem Biol 8:2372–2376

    Article  CAS  Google Scholar 

  • Waterhouse A, Bertoni M, Bienert S, Studer G, Tauriello G, Gumienny R, Heer FT, de Beer TAP, Rempfer C, Bordoli L, Lepore R, Schwede T (2018) SWISS-MODEL: homology modelling of protein structures and complexes. Nucl Acids Res 46:W296–W303

    Article  CAS  Google Scholar 

  • Xue C, Liang F, Mahmood R, Vuolo M, Wyckoff J, Qian H, Tsai KL, Kim M, Locker J, Zhang ZY, Segall JE (2006) ErbB3-dependent motility and intravasation in breast cancer metastasis. Cancer Res 66:1418–1426

    Article  CAS  Google Scholar 

  • Zhang X, Pickin KA, Bose R, Jura N, Cole PA, Kuriyan J (2007) Inhibition of the EGF receptor by binding of MIG6 to an activating kinase domain interface. Nature 450:741–744

    Article  CAS  Google Scholar 

  • Zhang Q, Jing T, Cui X, Zhao L (2021) Rational molecular profiling of receptor-associated late transducer peptide selectivity across Her/Rtk kinases. Int J Pept Res Ther 27:1945–1951

    Article  CAS  Google Scholar 

  • Zheng W, Lan J, Feng L, Chen Z, Feng S, Gao Y, Ren F, Chen Y (2020) Structure-based optimization of conformationally constrained peptides to target esophageal cancer TEAD transcription factor. Int J Pept Res Ther 27:923–930

    Article  Google Scholar 

  • Zhou P, Jin B, Li H, Huang SY (2018) HPEPDOCK: a web server for blind peptide-protein docking based on a hierarchical algorithm. Nucl Acids Res 46:W443–W450

    Article  CAS  Google Scholar 

  • Zhou P, Miao Q, Yan F, Li Z, Jiang Q, Wen L, Meng Y (2019) Is protein context responsible for peptide-mediated interactions? Mol Omics 15:280–295

    Article  CAS  Google Scholar 

  • Zhou P, Wang H, Chen Z, Liu Q (2021a) Context contribution to the intermolecular recognition of human ACE2-derived peptides by SARS-CoV-2 spike protein: implications for improving the peptide affinity but not altering the peptide specificity by optimizing indirect readout. Mol Omics 17:86–94

    Article  CAS  Google Scholar 

  • Zhou P, Yan F, Miao Q, Chen Z, Wang H (2021b) Why the first self-binding peptide of human c-Src kinase does not contain class II motif but can bind to its cognate Src homology 3 domain in class II mode? J Biomol Struct Dyn 39:310–318

    Article  CAS  Google Scholar 

  • Zhou P, Liu Q, Wu T, Miao Q, Shang S, Wang H, Chen Z, Wang S, Wang H (2021c) Systematic comparison and comprehensive evaluation of 80 amino acid descriptors in peptide QSAR modeling. J Chem Inf Model 61:1718–1731

    Article  CAS  Google Scholar 

  • Zhong H, He J, Yu J, Li X, Mei Y, Hao L, Wu X (2021) Mig6 not only inhibits EGFR and HER2 but also targets HER3 and HER4 in a differential specificity: implications for targeted esophageal cancer therapy. Biochimie 190:132–142

    Article  CAS  Google Scholar 

  • Zor T, De Guzman RN, Dyson HJ, Wright PE (2004) Solution structure of the KIX domain of CBP bound to the transactivation domain of c-Myb. J Mol Biol 337:521–534

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Xiamen Science and Technology Project (No. 3502Z20184048).

Author information

Author notes

  1. Chenghong Ji and Jianmin Zhuang have contributed equally to this work.

Authors and Affiliations

  1. Department of General Surgery, Xiamen Haicang Hospital, Xiamen, 361026, China

    Chenghong Ji, Jianmin Zhuang, Yizhou Jiang, Jiangang Mu & Longhai Lin

  2. Department of Medical Oncology, Xiamen Haicang Hospital, Xiamen, 361026, China

    Yide Chen

Authors
  1. Chenghong Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jianmin Zhuang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yizhou Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jiangang Mu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Longhai Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yide Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yide Chen.

Ethics declarations

Conflict of interest

None.

Human and Animal Rights

Not applicable.

Informed Consent

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ji, C., Zhuang, J., Jiang, Y. et al. Making ERRFI1-Derived Peptides ‘Bindable’ to the Allosteric Dimerization Interface of Breast Cancer ERBB3 Kinase by Adding a Nonbonded Interaction System. Int J Pept Res Ther 27, 2895–2904 (2021). https://doi.org/10.1007/s10989-021-10298-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10989-021-10298-6

Keywords

Search

Navigation