Conformational landscape of the epidermal growth factor receptor kinase reveals a mutant specific allosteric pocket

Kannan, Srinivasaraghavan; Venkatachalam, Gireedhar; Lim, Hong Hwa; Surana, Uttam; Verma, Chandra

doi:10.1039/c8sc01262h

Cited by 36 publications

(28 citation statements)

References 33 publications

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“…We focused on all diverse acquired mutations at the binding sites, exploring the binding site flexibility of EGFR kinase domains with the del746-750/T790M/C797S/ mutation and the L858R/T790M/C797S mutations by using µs-scale molecular dynamics (MD). MD simulation has been successfully applied to study the EGFR conformation space at a computational physiological environment [21][22][23][24] . For example, Park et.…”

Section: Introductionmentioning

confidence: 99%

Structural Insights into Characterizing Binding Sites in Epidermal Growth Factor Receptor Kinase Mutants

Zhao

Xie

Bourne

2018

J. Chem. Inf. Model.

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Over the last two decades epidermal growth factor receptor (EGFR) kinase has become an important target to treat non-small cell lung cancer (NSCLC). Currently, three generations of EGFR kinase-targeted small molecule drugs have been FDA approved. They nominally produce a response at the start of treatment and lead to a substantial survival benefit for patients. However, long-term treatment results in acquired drug resistance and further vulnerability to NSCLC.Therefore, novel EGFR kinase inhibitors that specially overcome acquired mutations are urgently needed. To this end, we carried out a comprehensive study of different EGFR kinase mutants using a structural systems pharmacology strategy. Our analysis shows that both wild-type and mutated structures exhibit multiple conformational states that have not been observed in solved crystal structures. We show that this conformational flexibility accommodates diverse types of ligands with multiple types of binding modes. These results provide insights for designing a newgeneration of EGFR kinase inhibitor that combats acquired drug-resistant mutations through a multi-conformation-based drug design strategy.

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Section: Introductionmentioning

confidence: 99%

Structural Insights into Characterizing Binding Sites in Epidermal Growth Factor Receptor Kinase Mutants

Zhao

Xie

Bourne

2018

J. Chem. Inf. Model.

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“…The findings suggested that, in combination with anti-EGFR antibodies such as cetuximab, 4th generation inhibitors could overcome resistance to the triple L834R/T766M/C773 mutation, which is resistant to all current EGFR-targeted therapies. Recent MD simulations have investigated the structural basis underlying the binding of 4th generation inhibitors [167]. The results revealed that the conformational destabilization of the short helix that carries Leu834 in the wild type exposes the allosteric pocket, which is otherwise occluded by a set of sidechains including L834.…”

Section: Kinase Domain Conformations and Their Coupling To Tyrosinmentioning

confidence: 99%

Structure and Dynamics of the EGF Receptor as Revealed by Experiments and Simulations and Its Relevance to Non-Small Cell Lung Cancer

Martin-Fernandez

Clarke

Roberts

et al. 2019

Cells

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The epidermal growth factor receptor (EGFR) is historically the prototypical receptor tyrosine kinase, being the first cloned and the first where the importance of ligand-induced dimer activation was ascertained. However, many years of structure determination has shown that EGFR is not completely understood. One challenge is that the many structure fragments stored at the PDB only provide a partial view because full-length proteins are flexible entities and dynamics play a key role in their functionality. Another challenge is the shortage of high-resolution data on functionally important higher-order complexes. Still, the interest in the structure/function relationships of EGFR remains unabated because of the crucial role played by oncogenic EGFR mutants in driving non-small cell lung cancer (NSCLC). Despite targeted therapies against EGFR setting a milestone in the treatment of this disease, ubiquitous drug resistance inevitably emerges after one year or so of treatment. The magnitude of the challenge has inspired novel strategies. Among these, the combination of multi-disciplinary experiments and molecular dynamic (MD) simulations have been pivotal in revealing the basic nature of EGFR monomers, dimers and multimers, and the structure-function relationships that underpin the mechanisms by which EGFR dysregulation contributes to the onset of NSCLC and resistance to treatment.

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“…As one of the most efficient and precise paradigms to tweak proteins’ functional activity and an important supplement to the traditional orthosteric-targeting strategy, allosteric modulators by targeting allosteric sites have enhanced specificity and reduced adverse effects, thereby presenting a promising avenue for modern drug development [ 4 , 5 , 6 ]. The latest decade has witnessed the upsurge of structural biology and protein allostery research, which led to inspiring success in allosteric drug discovery throughout an extended list of critical therapeutic targets such as kinases [ 7 , 8 , 9 ], Ras [ 10 , 11 , 12 , 13 , 14 ], and G-protein-coupled receptors [ 15 , 16 ], proving the enormous potential of allosteric regulation.…”

Section: Introductionmentioning

confidence: 99%

Untangling Dual-Targeting Therapeutic Mechanism of Epidermal Growth Factor Receptor (EGFR) Based on Reversed Allosteric Communication

et al. 2021

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Dual-targeting therapeutics by coadministration of allosteric and orthosteric drugs is drawing increased attention as a revolutionary strategy for overcoming the drug-resistance problems. It was further observed that the occupation of orthosteric sites by therapeutics agents has the potential to enhance allosteric ligand binding, which leads to improved potency of allosteric drugs. Epidermal growth factor receptor (EGFR), as one of the most critical anti-cancer targets belonging to the receptor tyrosine kinase family, represents a quintessential example. It was revealed that osimertinib, an ATP-competitive covalent EGFR inhibitor, remarkably enhanced the affinity of a recently developed allosteric inhibitor JBJ-04-125-02 for EGFRL858R/T790M. Here, we utilized extensive large-scale molecular dynamics simulations and the reversed allosteric communication to untangle the detailed molecular underpinning, in which occupation of osimertinib at the orthosteric site altered the overall conformational ensemble of EGFR mutant and reshaped the allosteric site via long-distance signaling. A unique intermediate state resembling the active conformation was identified, which was further stabilized by osimertinib loading. Based on the allosteric communication pathway, we predicted a novel allosteric site positioned around K867, E868, H893, and K960 within the intermediate state. Its correlation with the orthosteric site was validated by both structural and energetic analysis, and its low sequence conservation indicated the potential for selective targeting across the human kinome. Together, these findings not only provided a mechanistic basis for future clinical application of the dual-targeting therapeutics, but also explored an innovative perception of allosteric inhibition of tyrosine kinase signaling.

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Conformational landscape of the epidermal growth factor receptor kinase reveals a mutant specific allosteric pocket

Abstract: An oncogenic mutant-specific druggable allosteric pocket captured by MD simulations.

Cited by 36 publications

References 33 publications

Structural Insights into Characterizing Binding Sites in Epidermal Growth Factor Receptor Kinase Mutants

Structural Insights into Characterizing Binding Sites in Epidermal Growth Factor Receptor Kinase Mutants

Structure and Dynamics of the EGF Receptor as Revealed by Experiments and Simulations and Its Relevance to Non-Small Cell Lung Cancer

Untangling Dual-Targeting Therapeutic Mechanism of Epidermal Growth Factor Receptor (EGFR) Based on Reversed Allosteric Communication

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