Dataset Information

Targeting of disease-linked mutations in PI3K gamma

ABSTRACT: Using hydrogen deuterium exchange mass spectrometry (HDX-MS) and molecular dynamics we have identified mutation specific conformational changes, and provide a molecular framework for how they alter kinase activity.Many of the activating conformational changes mimicked previously described changes that occur upon membrane binding and allosteric inhibitor binding. We surveyed a diverse panel of PI3K inhibitors using HDX-MS and X-ray crystallography, and find that inhibitors that interact with the activation loop lead to allosteric conformational changes that partially mimic the R1021C mutation. Intriguingly, inhibitors that showed similar conformational changes to the activating mutant showed increased potency (~3 fold) for the mutant over wild type PI3K. Overall this work provides unique insight into the regulatory mechanisms that control PI3K kinase activity, and reveals a framework for the potential design of PI3K isoform and mutant selective inhibitors.

INSTRUMENT(S): impact HD

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: John Burke

LAB HEAD: Dr. John E Burke

PROVIDER: PXD021132 | Pride | 2021-03-26

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	09_9_19_MRHDX19_A_3000s_1_0_01_11314.d.zip	Other
	09_9_19_MRHDX19_B_3000s_1_0_01_11316.d.zip	Other
	09_9_19_MRHDX19_C_3000s_1_0_01_11318.d.zip	Other
	09_9_19_MRHDX19_D_3000s_1_0_01_11320.d.zip	Other
	09_9_19_MRHDX19_E_3000s_1_0_01_11322.d.zip	Other

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Publications

Disease-related mutations in PI3Kγ disrupt regulatory C-terminal dynamics and reveal a path to selective inhibitors.

Rathinaswamy Manoj K MK Gaieb Zied Z Fleming Kaelin D KD Borsari Chiara C Harris Noah J NJ Moeller Brandon E BE Wymann Matthias P MP Amaro Rommie E RE Burke John E JE

eLife 20210304

Class I Phosphoinositide 3-kinases (PI3Ks) are master regulators of cellular functions, with the class IB PI3K catalytic subunit (p110γ) playing key roles in immune signalling. p110γ is a key factor in inflammatory diseases and has been identified as a therapeutic target for cancers due to its immunomodulatory role. Using a combined biochemical/biophysical approach, we have revealed insight into regulation of kinase activity, specifically defining how immunodeficiency and oncogenic mutations of ...[more]

PMID: 33661099

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