A rotamer relay information system in the epidermal growth factor receptor–drug complexes reveals clues to new paradigm in protein conformational change
| Autor: | Andrew D. Miller, Yazan Haddad, Vojtech Adam, Michal Mokry, Tareq Hameduh, Zbynek Heger |
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| Rok vydání: | 2021 |
| Předmět: |
Conformational change
medicine.drug_class EGFR Biophysics Tumour resistance Tyrosine kinase inhibitor NSCLC Biochemistry Tyrosine-kinase inhibitor 03 medical and health sciences 0302 clinical medicine Protein structure Structural Biology Genetics medicine Protein folding Epidermal growth factor receptor Conformational isomerism ComputingMethodologies_COMPUTERGRAPHICS 030304 developmental biology 0303 health sciences biology Kinase Chemistry Rotamer 3. Good health Computer Science Applications 030220 oncology & carcinogenesis biology.protein Tyrosine kinase TP248.13-248.65 Research Article Biotechnology |
| Zdroj: | Computational and Structural Biotechnology Journal, Vol 19, Iss, Pp 5443-5454 (2021) Computational and Structural Biotechnology Journal. 2021, vol. 19, issue 1, p. 5443-5454. Computational and Structural Biotechnology Journal |
| ISSN: | 2001-0370 |
| DOI: | 10.1016/j.csbj.2021.09.026 |
| Popis: | Graphical abstract Highlights • EGFR kinase C-helix moves relate to side chain rotamers of 43 residues. • Rotamer changes formed several clusters as part of two major information relays. • Relay-IN identifies rotamers in active C-helix-IN/DFGin/BLAminus conformations. • Triple mutants were in Relay-OUT with inactive C-helix-OUT/DFGout/BBAminus. • Global rotamer moves can impact kinase activation and tumour resistance. Cancer cells can escape the effects of chemotherapy through mutations and upregulation of a tyrosine kinase protein called the epidermal growth factor receptor (EGFR). In the past two decades, four generations of tyrosine kinase inhibitors targeting EGFR have been developed. Using comparative structure analysis of 116 EGFR-drug complex crystal structures, cluster analysis produces two clans of 73 and 43 structures, respectively. The first clan of 73 structures is larger and is comprised mostly of the C-helix-IN conformation while the second clan of 43 structures correlates with the C-helix-OUT conformation. A deep rotamer analysis identifies 43 residues (18%) of the total of 237 residues spanning the kinase structures under investigation with significant rotamer variations between the C-helix-IN and C-helix-OUT clans. The locations of these rotamer variations take on the appearance of side chain conformational relays extending out from points of EGFR mutation to different regions of the EGFR kinase. Accordingly, we propose that key EGFR mutations act singly or together to induce drug resistant conformational changes in EGFR that are communicated via these side chain conformational relays. Accordingly, these side chain conformational relays appear to play a significant role in the development of tumour resistance. This phenomenon also suggests a new paradigm in protein conformational change that is mediated by supportive relays of rotamers on the protein surface, rather than through conventional backbone movements. |
| Databáze: | OpenAIRE |
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