Discovery of cryptic allosteric sites using reversed allosteric communication by a combined computational and experimental strategy

Ni, Duan; Wei, Jiacheng; He, Xinheng; Rehman, Ashfaq Ur; Li, Xinyi; Qiu, Yuran; Pu, Jun; Lu, Shaoyong; Zhang, Jian

doi:10.1039/d0sc05131d

Cited by 97 publications

(102 citation statements)

References 84 publications

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“…Therefore, it was illustrated that osimertinib binding stabilized the allosteric X-pocket in a deepened state with the open A loop, thus contributing to ligand targeting. Since the volume calculation results only deciphered structural coupling between the allosteric and orthosteric sites, we further exploited a recently established quantitative algorithm to delineate the crosstalk in the view of energetics [28]. The calculation model arose from the reversed allosteric communication theory that the free energies of a proportion of residue-residue interactions within the allosteric sites undergo considerable changes due to orthosteric perturbations.…”

Section: Identification Of Potential Allosteric Pockets Based On Revementioning

confidence: 99%

“…This theory has been validated in several studies as examined with a series of classical allosteric proteins, including 15-lipoxygenase [ 27 ] and protein kinase 1 [ 23 ], and further promoted the discovery of several novel allosteric sites. Recently, based on the reversed allosteric communication, we have developed a combined computational and experimental strategy to discover cryptic allosteric sites of sirtuin 6 (SIRT6), providing a starting point for SIRT6 allosteric drug design [ 28 ]. Herein, we hypothesized that the altered efficacy of allosteric inhibitors observed in experiments was attributed to reversed allosteric communication, whereby the conformation of allosteric sites can be shifted by perturbations at the functional sites, contributing to the emergence or stabilization of allosteric pockets.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Identification Of Potential Allosteric Pockets Based On Revementioning

confidence: 99%

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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“…However, unravelling of a large number of Ras structures and development of computational methods for protein structural investigations, in the last decade, have led to enormous breakthroughs in our understanding of Ras conformational dynamics and Ras-regulator/effector protein–protein interactions (PPIs) [14] , [22] , [23] , [24] , [25] . These developments have renewed structure-based drug design strategies [26] , [27] , [28] , such as identification of cryptic allosteric sites in Ras and inhibition of Ras complexation with regulators or effectors [29] , [30] . Attempts at targeting the ‘undruggable’ Ras have yielded several preliminary successes so far.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic insights into the effect of phosphorylation on Ras conformational dynamics and its interactions with cell signaling proteins

Wang

Lei

et al. 2021

Computational and Structural Biotechnology Journal

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“…The dynamic cross-correlation matrix (DCCM) of all protein Ca atoms were calculated to reflect the inter-residue correlations [36][37][38][39][40]. The cross-correlation coefficient C ij was calculated by:…”

Section: Dynamic Cross-correlation Matrix (Dccm) Analysismentioning

confidence: 99%

Deciphering the resistance mechanism of RET kinase mutant against vandetanib and nintedanib using molecular dynamics simulations

Zheng

Liu

et al. 2021

Journal of Experimental Nanoscience

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The RET protein is a transmembrane receptor tyrosine kinase (RTK) whose oncogenic mutations or fusions are closely related to human cancers such as thyroid and non-small cell lung cancer. Vandetanib as a clinical-approved protein-tyrosine kinase inhibitor (TKI) exhibits anti-cancer efficacy by blocking the RET ATP-binding site, but drug resistance was observed for the RET G810A mutant. Recent studies have identified another TKI nintedanib as an effective molecule to inhibit vandetanib-resistant RET G810A . However, there is no clear evidence of why nintedanib and vandetanib displayed different inhibitory activities towards RET G810A . Here, we exploited molecular dynamic (MD) simulations to compare the interactions of the RET G810A mutant with nintedanib and vandetanib. A higher structural flexibility of the activation loop was observed in the nintedanib-bound RET G810A , which may result in discrepant autophosphorylation activity in the nintedanib-and vandetanib-bound RET kinase, causing differentiated pharmacological effects of the two compounds. Molecular mechanics/Poisson-Bolzmann surface area method suggested that nintedanib had a higher affinity towards RET G810A over vandetanib, accounting for its better inhibitory effect as an ATP-competitive compound. These results depicted the underlying mechanism for the different inhibitory efficacy of nintedanib and vandetanib on RET G810A from both conformational and energetic aspects. Furthermore, we also found that both compounds maintained the 'DFG-in, aC-helix-in, and activation loopopen' conformation of RET G810A , which is the characteristic of the active state. Together, our results provide comprehensive mechanistic insights into nintedanib's capability in inhibiting vandetanibresistant RET mutant and enlighten future structural-based optimisation of RET TKIs to overcome drug resistance.

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Discovery of cryptic allosteric sites using reversed allosteric communication by a combined computational and experimental strategy

Abstract: Allostery, which is one of the most direct and efficient methods to fine-tune protein functions, has gained increasing recognition in drug discovery. However, there are several challenges associated with the...

Cited by 97 publications

References 84 publications

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

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

Mechanistic insights into the effect of phosphorylation on Ras conformational dynamics and its interactions with cell signaling proteins

Deciphering the resistance mechanism of RET kinase mutant against vandetanib and nintedanib using molecular dynamics simulations

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