Harnessing Allostery: A Novel Approach to Drug Discovery

Lu, Shaoyong; Li, Shuai; Zhang, Jian

doi:10.1002/med.21317

Cited by 125 publications

(99 citation statements)

References 221 publications

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“…Recent evidence indicates that ATP can also function as an allosteric modulator (Huang et al, 2014;Lu et al, 2014a). Thus, understanding the allosteric mechanism of ATP in Akt1 may provide broader insights into the role of ATP and its mechanism as an endogenous modulator in cell signaling and in an important class of enzymes (Nussinov and Tsai, 2013;Lu et al, 2014b).…”

Section: Discussionmentioning

confidence: 98%

The Mechanism of ATP-Dependent Allosteric Protection of Akt Kinase Phosphorylation

Deng

Jiang

et al. 2015

Structure

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Kinases use ATP to phosphorylate substrates; recent findings underscore the additional regulatory roles of ATP. Here, we propose a mechanism for allosteric regulation of Akt1 kinase phosphorylation by ATP. Our 4.7-μs molecular dynamics simulations of Akt1 and its mutants in the ATP/ADP bound/unbound states revealed that ATP occupancy of the ATP-binding site stabilizes the closed conformation, allosterically protecting pT308 by restraining phosphatase access and key interconnected residues on the ATP→pT308 allosteric pathway. Following ATP→ADP hydrolysis, pT308 is exposed and readily dephosphorylated. Site-directed mutagenesis validated these predictions and indicated that the mutations do not impair PDK1 and PP2A phosphatase recruitment. We further probed the function of residues around pT308 at the atomic level, and predicted and experimentally confirmed that Akt1(H194R/R273H) double mutant rescues pathology-related Akt1(R273H). Analysis of classical Akt homologs suggests that this mechanism can provide a general model of allosteric kinase regulation by ATP; as such, it offers a potential avenue for allosteric drug discovery.

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Section: Discussionmentioning

confidence: 98%

The Mechanism of ATP-Dependent Allosteric Protection of Akt Kinase Phosphorylation

Deng

Jiang

et al. 2015

Structure

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“…Most of the residues that are perturbed significantly are in the vicinity of the P-loop (residues 10 -17) where the G12D mutation is located, suggesting that the G12D mutation alters the conformation of the functional P-loop, switch I and switch II regions. Remarkably, G12D can also perturb the HVR, which is relatively far away from the P-loop, indicating that the G12D mutation affects the HVRcatalytic domain interactions by longer range interactions (45)(46)(47).…”

Section: Specific Oncogenic Mutations May Weaken the Hvr-catalytic Domentioning

confidence: 99%

GTP Binding and Oncogenic Mutations May Attenuate Hypervariable Region (HVR)-Catalytic Domain Interactions in Small GTPase K-Ras4B, Exposing the Effector Binding Site

Banerjee²,

Jang

et al. 2015

Journal of Biological Chemistry

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Background:The HVR is important in K-Ras4B signaling. Results: GTP binding and oncogenic mutations may weaken the HVR-catalytic core interactions. Conclusion: GTP and some oncogenic mutations (e.g. G12C/G12V/Q61H/E37K) could attenuate HVR-catalytic domain interactions at the switch I/effector binding site by direct or longer-range interactions. Significance: GTP and specific mutations could prompt exposure of switch I/effector binding site, thereby up-regulating signaling.

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“…Rapalogs, as allosteric inhibitors of mTORC1, were approved for advanced renal cell cancer, pancreatic neuroendocrine tumors, and subependymal giant-cell astrocytoma associated with tuberous sclerosis [31,42]. There is an extreme increase in the discovery and development of allosteric drugs [43].…”

Section: Allosteric Drugsmentioning

confidence: 99%

Allosteric therapies for lung cancer

Jing

Wang

2015

Cancer Metastasis Rev

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Allostery is a regulation at a distance by conveying information from one site to another and an intrinsic property of dynamic proteins. Allostery plays an essential role in receptor trafficking, signal transmission, controlled catalysis, gene turn on/off, or cell apoptosis. Allosteric mutations are considered as one of causes responsible for cancer development, leading to "allosteric diseases" by stabilizing an active or inactive conformation or changing the dynamic distribution of preexisting propagation pathways. The present article mainly focuses on the potential of allosteric therapies for lung cancer. Allosteric drugs may have several advantages over traditional drugs. The epidermal growth factor receptor mutations and signaling pathways downstream (such as PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways) were suggested to play a key role in lung cancer and considered as targets of allosteric therapy. Some allosteric inhibitors for lung cancer-specific targets and a series of preclinical trials of allosteric inhibitors for lung cancer have been developed and reported. We expect that allosteric therapies will gain more attentions to develop combinatorial strategies for lung cancer and metastasis.

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Harnessing Allostery: A Novel Approach to Drug Discovery

Cited by 125 publications

References 221 publications

The Mechanism of ATP-Dependent Allosteric Protection of Akt Kinase Phosphorylation

The Mechanism of ATP-Dependent Allosteric Protection of Akt Kinase Phosphorylation

GTP Binding and Oncogenic Mutations May Attenuate Hypervariable Region (HVR)-Catalytic Domain Interactions in Small GTPase K-Ras4B, Exposing the Effector Binding Site

Allosteric therapies for lung cancer

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