Ca2+-based allosteric switches and shape shifting in RGLG1 VWA domain

Wang, Qin; Chen, YaYu; Li, Shengping; Yang, Wendi; Sun, Lifang; Jang, M.; Wu, Xiang-Feng; Wang, Qianchao; Chen, Lifei; Wu, Yunkun

doi:10.1016/j.csbj.2020.03.023

Cited by 7 publications

(6 citation statements)

References 49 publications

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“…In the last decades, the long-term impetus has promoted innovative attempts to tackle the elusive enigma with multidisciplinary approaches. With accumulating evidence of the multiple advantages boosted by allosteric modulation, it has attracted an ever-growing interest in pharmaceutics, and consequently, the combination of orthosteric and allosteric agents is emerging as a revolutionary strategy to overcome resistance, as exemplified by the growing number of successful cases [ 74 , 75 , 76 , 77 , 78 , 79 ]. Accordingly, a series of orthosteric-allosteric drug combinations have proceeded into clinical trials, mostly involving oncology, viruses, and autoimmune disorders [ 17 ].…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…[1][2][3][4][5] Allosteric regulation is characterized by the existence of biophysical coupling between orthosteric sites and topologically distal allosteric sites, in which perturbations at allosteric sites, such as ligand binding, residue mutations, and post-translational modifications, fine-tune orthosteric sites. [6][7][8][9][10][11][12][13][14] In theory, all non-fibrous proteins are allosteric, and decades of exploration have unveiled the widespread prevalence of allosteric regulation in a plethora of biochemical and cellular events under both physiological and pathological conditions. 7,[15][16][17][18][19][20][21][22][23][24][25] Their involvement facilitates the exquisite orchestration of innumerable biological processes and is an emerging paradigm for drug discovery.…”

Section: Introductionmentioning

confidence: 99%

“…Such a concept, referred to as “allosteric regulation” or “allosterism” was further defined by Changeux et al in the 1960s 1–5 . Allosteric regulation is characterized by the existence of biophysical coupling between orthosteric sites and topologically distal allosteric sites, in which perturbations at allosteric sites, such as ligand binding, residue mutations, and post‐translational modifications, fine‐tune orthosteric sites 6–14 . In theory, all non‐fibrous proteins are allosteric, and decades of exploration have unveiled the widespread prevalence of allosteric regulation in a plethora of biochemical and cellular events under both physiological and pathological conditions 7,15–25 .…”

Section: Introductionmentioning

confidence: 99%

Along the allostery stream: Recent advances in computational methods for allosteric drug discovery

Chai

Wang

et al. 2021

WIREs Comput Mol Sci

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Allostery is a universal, biological phenomenon in which orthosteric sites are finetuned by topologically distal allosteric sites triggered by perturbations, such as ligand binding, residue mutations, or post-translational modifications. Allosteric regulation is implicated in a variety of physiological and pathological conditions and is thus emerging as a novel avenue for drug discovery. Allosteric drugs have traditionally been discovered by serendipity through large-scale experimental screening. Recently, we have witnessed significant progress in biophysics, particularly in structural bioinformatics, which has facilitated the in-depth characterization of allosteric effects and the accurate detection of allosteric residues and exosites. These advances improve our understanding of allosterism and promote allosteric drug discovery, thereby revolutionizing the shift from the traditional serendipitous route used to discover allosteric drugs to the updated path centered on rational structure-based design. In this review, recent advances in computational methods applied to allosteric drug discovery are summarized. We comprehensively review these achievements along various levels of allosteric events, from the construction of allosteric databases to the identification and analysis of allosteric residues, signals, sites, and modulators. We expect to increase the awareness of the discovery of allosteric drugs using structure-based computational methods.

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“…Allostery, or allosteric regulation, is a fundamental and common mechanism of intramolecular signal transmission, where the structure and dynamics of orthosteric sites are fine-tuned by local perturbations at other topographically distal sites (defined as allosteric sites) through dynamic effects with the conformational ensembles of biomacromolecules. − Allosteric regulation plays a pivotal role in tweaking a variety of biological processes, such as signal transduction, cellular metabolism, enzyme catalysis, and gene regulation, , and is thus considered the “the second secret of life” . Allosteric drugs possess several significant advantages over traditional orthosteric drugs, including greater selectivity, better physicochemical properties, and lower off-target toxicity, and thus represent a new paradigm for modern innovative drug design. − …”

Section: Introductionmentioning

confidence: 99%

Harnessing Reversed Allosteric Communication: A Novel Strategy for Allosteric Drug Discovery

et al. 2021

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Allostery is a fundamental and extensive mechanism of intramolecular signal transmission. Allosteric drugs possess several unique pharmacological advantages over traditional orthosteric drugs, including greater selectivity, better physicochemical properties, and lower off-target toxicity. However, owing to the complexity of allosteric regulation, experimental approaches for the development of allosteric modulators are traditionally serendipitous. Recently, the reversed allosteric communication theory has been proposed, providing a feasible tool for the unbiased detection of allosteric sites. Herein, we review the latest research on the reversed allosteric communication effect using the examples of sirtuin 6, epidermal growth factor receptor, 3-phosphoinositide-dependent protein kinase 1, and Related to A and C kinases (RAC) serine/threonine protein kinase B and recapitulate the methodologies of reversed allosteric communication strategy. The novel reversed allosteric communication strategy greatly expands the horizon of allosteric site identification and allosteric mechanism exploration and is expected to accelerate an end-to-end framework for drug discovery.

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Ca2+-based allosteric switches and shape shifting in RGLG1 VWA domain

Cited by 7 publications

References 49 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

Along the allostery stream: Recent advances in computational methods for allosteric drug discovery

Harnessing Reversed Allosteric Communication: A Novel Strategy for Allosteric Drug Discovery

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