Disease-related mutations in PI3Kγ disrupt regulatory C-terminal dynamics and reveal a path to selective inhibitors
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 immun...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2021-03-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/64691 |
| id |
doaj-7f784cecc93e43a98a6ad064bf0019ce |
|---|---|
| record_format |
Article |
| spelling |
doaj-7f784cecc93e43a98a6ad064bf0019ce2021-05-05T22:51:46ZengeLife Sciences Publications LtdeLife2050-084X2021-03-011010.7554/eLife.64691Disease-related mutations in PI3Kγ disrupt regulatory C-terminal dynamics and reveal a path to selective inhibitorsManoj K Rathinaswamy0https://orcid.org/0000-0001-5909-4353Zied Gaieb1Kaelin D Fleming2Chiara Borsari3https://orcid.org/0000-0002-4688-8362Noah J Harris4Brandon E Moeller5Matthias P Wymann6https://orcid.org/0000-0003-3349-4281Rommie E Amaro7John E Burke8https://orcid.org/0000-0001-7904-9859Department of Biochemistry and Microbiology, University of Victoria, Victoria, CanadaDepartment of Chemistry and Biochemistry, University of California San Diego, San Diego, United StatesDepartment of Biochemistry and Microbiology, University of Victoria, Victoria, CanadaUniversity of Basel, Department of Biomedicine, Basel, SwitzerlandDepartment of Biochemistry and Microbiology, University of Victoria, Victoria, CanadaDepartment of Biochemistry and Microbiology, University of Victoria, Victoria, CanadaUniversity of Basel, Department of Biomedicine, Basel, SwitzerlandDepartment of Chemistry and Biochemistry, University of California San Diego, San Diego, United StatesDepartment of Biochemistry and Microbiology, University of Victoria, Victoria, Canada; Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, CanadaClass 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 R1021 in the C-terminus can inactivate or activate enzyme activity. Screening of inhibitors using HDX-MS revealed that activation loop-binding inhibitors induce allosteric conformational changes that mimic those in the R1021C mutant. Structural analysis of advanced PI3K inhibitors in clinical development revealed novel binding pockets that can be exploited for further therapeutic development. Overall, this work provides unique insights into regulatory mechanisms that control PI3Kγ kinase activity and shows a framework for the design of PI3K isoform and mutant selective inhibitors.https://elifesciences.org/articles/64691PI3Khydrogen exchangeHDX-MSmolecular dynamicsPIK3CGkinases |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Manoj K Rathinaswamy Zied Gaieb Kaelin D Fleming Chiara Borsari Noah J Harris Brandon E Moeller Matthias P Wymann Rommie E Amaro John E Burke |
| spellingShingle |
Manoj K Rathinaswamy Zied Gaieb Kaelin D Fleming Chiara Borsari Noah J Harris Brandon E Moeller Matthias P Wymann Rommie E Amaro John E Burke Disease-related mutations in PI3Kγ disrupt regulatory C-terminal dynamics and reveal a path to selective inhibitors eLife PI3K hydrogen exchange HDX-MS molecular dynamics PIK3CG kinases |
| author_facet |
Manoj K Rathinaswamy Zied Gaieb Kaelin D Fleming Chiara Borsari Noah J Harris Brandon E Moeller Matthias P Wymann Rommie E Amaro John E Burke |
| author_sort |
Manoj K Rathinaswamy |
| title |
Disease-related mutations in PI3Kγ disrupt regulatory C-terminal dynamics and reveal a path to selective inhibitors |
| title_short |
Disease-related mutations in PI3Kγ disrupt regulatory C-terminal dynamics and reveal a path to selective inhibitors |
| title_full |
Disease-related mutations in PI3Kγ disrupt regulatory C-terminal dynamics and reveal a path to selective inhibitors |
| title_fullStr |
Disease-related mutations in PI3Kγ disrupt regulatory C-terminal dynamics and reveal a path to selective inhibitors |
| title_full_unstemmed |
Disease-related mutations in PI3Kγ disrupt regulatory C-terminal dynamics and reveal a path to selective inhibitors |
| title_sort |
disease-related mutations in pi3kγ disrupt regulatory c-terminal dynamics and reveal a path to selective inhibitors |
| publisher |
eLife Sciences Publications Ltd |
| series |
eLife |
| issn |
2050-084X |
| publishDate |
2021-03-01 |
| description |
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 R1021 in the C-terminus can inactivate or activate enzyme activity. Screening of inhibitors using HDX-MS revealed that activation loop-binding inhibitors induce allosteric conformational changes that mimic those in the R1021C mutant. Structural analysis of advanced PI3K inhibitors in clinical development revealed novel binding pockets that can be exploited for further therapeutic development. Overall, this work provides unique insights into regulatory mechanisms that control PI3Kγ kinase activity and shows a framework for the design of PI3K isoform and mutant selective inhibitors. |
| topic |
PI3K hydrogen exchange HDX-MS molecular dynamics PIK3CG kinases |
| url |
https://elifesciences.org/articles/64691 |
| work_keys_str_mv |
AT manojkrathinaswamy diseaserelatedmutationsinpi3kgdisruptregulatorycterminaldynamicsandrevealapathtoselectiveinhibitors AT ziedgaieb diseaserelatedmutationsinpi3kgdisruptregulatorycterminaldynamicsandrevealapathtoselectiveinhibitors AT kaelindfleming diseaserelatedmutationsinpi3kgdisruptregulatorycterminaldynamicsandrevealapathtoselectiveinhibitors AT chiaraborsari diseaserelatedmutationsinpi3kgdisruptregulatorycterminaldynamicsandrevealapathtoselectiveinhibitors AT noahjharris diseaserelatedmutationsinpi3kgdisruptregulatorycterminaldynamicsandrevealapathtoselectiveinhibitors AT brandonemoeller diseaserelatedmutationsinpi3kgdisruptregulatorycterminaldynamicsandrevealapathtoselectiveinhibitors AT matthiaspwymann diseaserelatedmutationsinpi3kgdisruptregulatorycterminaldynamicsandrevealapathtoselectiveinhibitors AT rommieeamaro diseaserelatedmutationsinpi3kgdisruptregulatorycterminaldynamicsandrevealapathtoselectiveinhibitors AT johneburke diseaserelatedmutationsinpi3kgdisruptregulatorycterminaldynamicsandrevealapathtoselectiveinhibitors |
| _version_ |
1721457526615048192 |