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Article ; Online: Gatekeeper mutations activate FGF receptor tyrosine kinases by destabilizing the autoinhibited state.

Besch, Alida / Marsiglia, William M / Mohammadi, Moosa / Zhang, Yingkai / Traaseth, Nathaniel J

Proceedings of the National Academy of Sciences of the United States of America

2023 Volume 120, Issue 8, Page(s) e2213090120

Abstract: Many types of human cancers are being treated with small molecule ATP-competitive inhibitors targeting the kinase domain of receptor tyrosine kinases. Despite initial successful remission, long-term treatment almost inevitably leads to the emergence of ... ...

Abstract	Many types of human cancers are being treated with small molecule ATP-competitive inhibitors targeting the kinase domain of receptor tyrosine kinases. Despite initial successful remission, long-term treatment almost inevitably leads to the emergence of drug resistance mutations at the gatekeeper residue hindering the access of the inhibitor to a hydrophobic pocket at the back of the ATP-binding cleft. In addition to reducing drug efficacy, gatekeeper mutations elevate the intrinsic activity of the tyrosine kinase domain leading to more aggressive types of cancer. However, the mechanism of gain-of-function by gatekeeper mutations is poorly understood. Here, we characterized fibroblast growth factor receptor (FGFR) tyrosine kinases harboring two distinct gatekeeper mutations using kinase activity assays, NMR spectroscopy, bioinformatic analyses, and MD simulations. Our data show that gatekeeper mutations destabilize the autoinhibitory conformation of the DFG motif locally and of the kinase globally, suggesting they impart gain-of-function by facilitating the kinase's ability to populate the active state.
MeSH term(s)	Humans ; Receptor Protein-Tyrosine Kinases ; Receptors, Fibroblast Growth Factor/genetics ; Neoplasms/drug therapy ; Mutation ; Adenosine Triphosphate/therapeutic use ; Tyrosine ; Protein Kinase Inhibitors/chemistry
Chemical Substances	Receptor Protein-Tyrosine Kinases (EC 2.7.10.1) ; Receptors, Fibroblast Growth Factor ; Adenosine Triphosphate (8L70Q75FXE) ; Tyrosine (42HK56048U) ; Protein Kinase Inhibitors
Language	English
Publishing date	2023-02-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2213090120
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Article ; Online: Live-cell target engagement of allosteric MEKi on MEK-RAF/KSR-14-3-3 complexes.

Marsiglia, William M / Chow, Arthur / Khan, Zaigham M / He, Liu / Dar, Arvin C

Nature chemical biology

2023 Volume 20, Issue 3, Page(s) 373–381

Abstract: The RAS-mitogen-activated protein kinase (MAPK) pathway includes KSR, RAF, MEK and the phospho-regulatory sensor 14-3-3. Specific assemblies among these components drive various diseases and likely dictate efficacy for numerous targeted therapies, ... ...

Abstract	The RAS-mitogen-activated protein kinase (MAPK) pathway includes KSR, RAF, MEK and the phospho-regulatory sensor 14-3-3. Specific assemblies among these components drive various diseases and likely dictate efficacy for numerous targeted therapies, including allosteric MEK inhibitors (MEKi). However, directly measuring drug interactions on physiological RAS-MAPK complexes in live cells has been inherently challenging to query and therefore remains poorly understood. Here we present a series of NanoBRET-based assays to quantify direct target engagement of MEKi on MEK1 and higher-order MEK1-bound complexes with ARAF, BRAF, CRAF, KSR1 and KSR2 in the presence and absence of 14-3-3 in living cells. We find distinct MEKi preferences among these complexes that can be compiled to generate inhibitor binding profiles. Further, these assays can report on the influence of the pathogenic BRAF-V600E mutant on MEKi binding. Taken together, these approaches can be used as a platform to screen for compounds intended to target specific complexes in the RAS-MAPK cascade.
MeSH term(s)	Proto-Oncogene Proteins B-raf/genetics ; Biological Assay ; MAP Kinase Signaling System ; Protein Kinase Inhibitors/pharmacology
Chemical Substances	Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; Protein Kinase Inhibitors
Language	English
Publishing date	2023-11-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	2202962-X
ISSN	1552-4469 ; 1552-4450
ISSN (online)	1552-4469
ISSN	1552-4450
DOI	10.1038/s41589-023-01454-8
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Article ; Online: Conformational control and regulation of the pseudokinase KSR via small molecule binding interactions.

Chow, Arthur / Khan, Zaigham M / Marsiglia, William M / Dar, Arvin C

Methods in enzymology

2022 Volume 667, Page(s) 365–402

Abstract: Pseudokinases often operate through functionally related enzymes and receptors. A prime example is the pseudokinase KSR (Kinase Suppressor of RAS), which can act as both an amplifier and inhibitor of members in the RAS-MAPK (Mitogen Activated Protein ... ...

Abstract	Pseudokinases often operate through functionally related enzymes and receptors. A prime example is the pseudokinase KSR (Kinase Suppressor of RAS), which can act as both an amplifier and inhibitor of members in the RAS-MAPK (Mitogen Activated Protein Kinase) signaling pathway. KSR is structurally related to the active RAF kinases over multiple domains; moreover, the pseudokinase domain of KSR forms physical and regulatory complexes with both RAF and MEK through distinct interfaces. Characterization of small molecule interactions on KSR has been used to uncover novel chemical tools and understand the mechanism of action of clinical drugs. Here, we elaborate on assays and structural methods for measuring binding at orthosteric and interfacial binding sites on KSR. These distinct small molecule pockets provide therapeutic paths for targeting KSR1 and KSR2 pseudokinases in disease, including in RAS and RAF mutant cancers.
MeSH term(s)	Binding Sites ; Molecular Conformation ; Phosphorylation ; Protein Kinases/chemistry ; Protein Serine-Threonine Kinases ; Proto-Oncogene Proteins c-raf/metabolism ; Signal Transduction
Chemical Substances	Protein Kinases (EC 2.7.-) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Proto-Oncogene Proteins c-raf (EC 2.7.11.1)
Language	English
Publishing date	2022-04-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1557-7988
ISSN (online)	1557-7988
DOI	10.1016/bs.mie.2022.03.039
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Article ; Online: Ploidy Leads a Molecular Motor to Walk Different Paths to Drug Resistance.

Real, Alexander M / Marsiglia, William M / Dar, Arvin C

Cell chemical biology

2020 Volume 27, Issue 7, Page(s) 770–772

Abstract: In this issue of Cell Chemical Biology, Pisa et al. (2020) find that haploid and diploid cells differentially develop resistance to the CENP-E inhibitor GSK923295. The results highlight the power of tumor cells to evade growth inhibition and potentially ... ...

Abstract	In this issue of Cell Chemical Biology, Pisa et al. (2020) find that haploid and diploid cells differentially develop resistance to the CENP-E inhibitor GSK923295. The results highlight the power of tumor cells to evade growth inhibition and potentially inform the design of next-generation CENP-E drugs to overcome resistance.
MeSH term(s)	Bridged Bicyclo Compounds, Heterocyclic ; Diploidy ; Drug Resistance ; Haploidy ; Humans ; Neoplasms
Chemical Substances	Bridged Bicyclo Compounds, Heterocyclic
Language	English
Publishing date	2020-07-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Comment
ISSN	2451-9448
ISSN (online)	2451-9448
DOI	10.1016/j.chembiol.2020.06.019
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Article: A CURE Biochemistry Laboratory Module to Study Protein-Protein Interactions by NMR Spectroscopy.

Marsiglia, William M / Qamra, Rohini / Jackson, Kimberly M / Traaseth, Nathaniel J

Journal of chemical education

2020 Volume 97, Issue 2, Page(s) 437–442

Abstract: Design of undergraduate laboratory courses that provide meaningful research-based experiences enhance undergraduate curricula and prepare future graduate students for research careers. In this article, a Course-based Undergraduate Research Experience ( ... ...

Abstract	Design of undergraduate laboratory courses that provide meaningful research-based experiences enhance undergraduate curricula and prepare future graduate students for research careers. In this article, a Course-based Undergraduate Research Experience (CURE) laboratory module was designed for upper-division undergraduate biochemistry and chemistry students. The laboratory module enabled students to build upon recently published data in the literature to decipher atomistic insight for an essential protein-protein interaction in human biology through the use of biomolecular NMR spectroscopy. Students compared their results with published data with the goal of identifying specific regions of the protein-protein interaction responsible for triggering an allosteric conformational change. The laboratory module introduced students to basic and advance laboratory techniques, including protein purification, NMR spectroscopy, and analysis of protein structure using molecular visualization software.
Language	English
Publishing date	2020-01-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	218164-2
ISSN	1938-1328 ; 0021-9584
ISSN (online)	1938-1328
ISSN	0021-9584
DOI	10.1021/acs.jchemed.9b00364
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Article ; Online: Multiple frequency saturation pulses reduce CEST acquisition time for quantifying conformational exchange in biomolecules.

Leninger, Maureen / Marsiglia, William M / Jerschow, Alexej / Traaseth, Nathaniel J

Journal of biomolecular NMR

2018 Volume 71, Issue 1, Page(s) 19–30

Abstract: Exchange between conformational states is required for biomolecular catalysis, allostery, and folding. A variety of NMR experiments have been developed to quantify motional regimes ranging from nanoseconds to seconds. In this work, we describe an ... ...

Abstract	Exchange between conformational states is required for biomolecular catalysis, allostery, and folding. A variety of NMR experiments have been developed to quantify motional regimes ranging from nanoseconds to seconds. In this work, we describe an approach to speed up the acquisition of chemical exchange saturation transfer (CEST) experiments that are commonly used to probe millisecond to second conformational exchange in proteins and nucleic acids. The standard approach is to obtain CEST datasets through the acquisition of a series of 2D correlation spectra where each experiment utilizes a single saturation frequency to
MeSH term(s)	Molecular Conformation ; Molecular Dynamics Simulation ; Motion ; Nuclear Magnetic Resonance, Biomolecular/methods ; Phospholipase C gamma/chemistry ; Proteins/chemistry ; Time Factors ; src Homology Domains
Chemical Substances	Proteins ; Phospholipase C gamma (EC 3.1.4.3)
Language	English
Publishing date	2018-05-23
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1081696-3
ISSN	1573-5001 ; 0925-2738
ISSN (online)	1573-5001
ISSN	0925-2738
DOI	10.1007/s10858-018-0186-1
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Zs.A 4132: Show issues

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Article ; Online: A Conserved Allosteric Pathway in Tyrosine Kinase Regulation.

Marsiglia, William M / Katigbak, Joseph / Zheng, Sijin / Mohammadi, Moosa / Zhang, Yingkai / Traaseth, Nathaniel J

Structure (London, England : 1993)

2019 Volume 27, Issue 8, Page(s) 1308–1315.e3

Abstract: An autoinhibitory network of hydrogen bonds located at the kinase hinge (referred to as the "molecular brake") regulates the activity of several receptor tyrosine kinases. The mechanism whereby mutational disengagement of the brake allosterically ... ...

Abstract	An autoinhibitory network of hydrogen bonds located at the kinase hinge (referred to as the "molecular brake") regulates the activity of several receptor tyrosine kinases. The mechanism whereby mutational disengagement of the brake allosterically activates the kinase in human disease is incompletely understood. We used a combination of NMR, bioinformatics, and molecular dynamics simulation to show that mutational disruption of the molecular brake triggers localized conformational perturbations that propagate to the active site. This entails changes in interactions of an isoleucine, one of three hydrophobic residues that lock the phenylalanine of the DFG motif in an inactive conformation. Structural analysis of tyrosine kinases provides evidence that this allosteric control mechanism is shared across the tyrosine kinase family. We also show that highly activating mutations at the brake diminish the enzyme's thermostability, thereby explaining why these mutations cause milder skeletal syndromes compared with less-activating mutations in the activation loop.
MeSH term(s)	Allosteric Regulation ; Catalytic Domain ; Humans ; Hydrophobic and Hydrophilic Interactions ; Isoleucine/genetics ; Magnetic Resonance Spectroscopy ; Molecular Dynamics Simulation ; Mutation ; Protein Conformation ; Protein-Tyrosine Kinases/chemistry ; Protein-Tyrosine Kinases/genetics
Chemical Substances	Isoleucine (04Y7590D77) ; Protein-Tyrosine Kinases (EC 2.7.10.1)
Language	English
Publishing date	2019-06-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1213087-4
ISSN	1878-4186 ; 0969-2126
ISSN (online)	1878-4186
ISSN	0969-2126
DOI	10.1016/j.str.2019.05.002
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Article ; Online: Structural basis for the action of the drug trametinib at KSR-bound MEK.

Khan, Zaigham M / Real, Alexander M / Marsiglia, William M / Chow, Arthur / Duffy, Mary E / Yerabolu, Jayasudhan R / Scopton, Alex P / Dar, Arvin C

Nature

2020 Volume 588, Issue 7838, Page(s) 509–514

Abstract: The MAPK/ERK kinase MEK is a shared effector of the frequent cancer drivers KRAS and BRAF that has long been pursued as a drug target in ... ...

Abstract	The MAPK/ERK kinase MEK is a shared effector of the frequent cancer drivers KRAS and BRAF that has long been pursued as a drug target in oncology
MeSH term(s)	Amino Acid Sequence ; Animals ; Binding Sites/drug effects ; Humans ; Mice ; Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors ; Mitogen-Activated Protein Kinase Kinases/chemistry ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Models, Molecular ; Protein Binding/drug effects ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology ; Protein Kinases/chemistry ; Protein Kinases/metabolism ; Pyridones/chemistry ; Pyridones/pharmacology ; Pyrimidinones/chemistry ; Pyrimidinones/pharmacology ; Substrate Specificity ; raf Kinases/chemistry ; raf Kinases/metabolism
Chemical Substances	Protein Kinase Inhibitors ; Pyridones ; Pyrimidinones ; trametinib (33E86K87QN) ; Protein Kinases (EC 2.7.-) ; KSR-1 protein kinase (EC 2.7.1.-) ; raf Kinases (EC 2.7.11.1) ; Mitogen-Activated Protein Kinase Kinases (EC 2.7.12.2)
Language	English
Publishing date	2020-09-14
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/s41586-020-2760-4
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Zs.A 26: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Molecular basis for receptor tyrosine kinase A-loop tyrosine transphosphorylation.

Chen, Lingfeng / Marsiglia, William M / Chen, Huaibin / Katigbak, Joseph / Erdjument-Bromage, Hediye / Kemble, David J / Fu, Lili / Ma, Jinghong / Sun, Gongqin / Zhang, Yingkai / Liang, Guang / Neubert, Thomas A / Li, Xiaokun / Traaseth, Nathaniel J / Mohammadi, Moosa

Nature chemical biology

2020 Volume 16, Issue 3, Page(s) 267–277

Abstract: A long-standing mystery shrouds the mechanism by which catalytically repressed receptor tyrosine kinase domains accomplish transphosphorylation of activation loop (A-loop) tyrosines. Here we show that this reaction proceeds via an asymmetric complex that ...

Abstract	A long-standing mystery shrouds the mechanism by which catalytically repressed receptor tyrosine kinase domains accomplish transphosphorylation of activation loop (A-loop) tyrosines. Here we show that this reaction proceeds via an asymmetric complex that is thermodynamically disadvantaged because of an electrostatic repulsion between enzyme and substrate kinases. Under physiological conditions, the energetic gain resulting from ligand-induced dimerization of extracellular domains overcomes this opposing clash, stabilizing the A-loop-transphosphorylating dimer. A unique pathogenic fibroblast growth factor receptor gain-of-function mutation promotes formation of the complex responsible for phosphorylation of A-loop tyrosines by eliminating this repulsive force. We show that asymmetric complex formation induces a more phosphorylatable A-loop conformation in the substrate kinase, which in turn promotes the active state of the enzyme kinase. This explains how quantitative differences in the stability of ligand-induced extracellular dimerization promotes formation of the intracellular A-loop-transphosphorylating asymmetric complex to varying extents, thereby modulating intracellular kinase activity and signaling intensity.
MeSH term(s)	AAA Domain/genetics ; AAA Domain/physiology ; Catalytic Domain ; Dimerization ; Enzyme Activation ; Humans ; Ligands ; Phosphorylation ; Protein Binding ; Protein Conformation ; Protein-Tyrosine Kinases/metabolism ; Protein-Tyrosine Kinases/physiology ; Receptor Protein-Tyrosine Kinases/genetics ; Receptor Protein-Tyrosine Kinases/metabolism ; Receptor Protein-Tyrosine Kinases/physiology ; Receptor, Fibroblast Growth Factor, Type 1/genetics ; Receptor, Fibroblast Growth Factor, Type 1/metabolism ; Receptor, Fibroblast Growth Factor, Type 2/genetics ; Receptor, Fibroblast Growth Factor, Type 2/metabolism ; Receptor, Fibroblast Growth Factor, Type 3/genetics ; Receptor, Fibroblast Growth Factor, Type 3/metabolism ; Signal Transduction ; Structure-Activity Relationship ; Tyrosine/chemistry
Chemical Substances	Ligands ; Tyrosine (42HK56048U) ; FGFR1 protein, human (EC 2.7.10.1) ; FGFR2 protein, human (EC 2.7.10.1) ; FGFR3 protein, human (EC 2.7.10.1) ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1) ; Receptor, Fibroblast Growth Factor, Type 1 (EC 2.7.10.1) ; Receptor, Fibroblast Growth Factor, Type 2 (EC 2.7.10.1) ; Receptor, Fibroblast Growth Factor, Type 3 (EC 2.7.10.1)
Language	English
Publishing date	2020-01-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2202962-X
ISSN	1552-4469 ; 1552-4450
ISSN (online)	1552-4469
ISSN	1552-4450
DOI	10.1038/s41589-019-0455-7
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Article ; Online: Structural and kinetic insights into stimulation of RppH-dependent RNA degradation by the metabolic enzyme DapF.

Gao, Ang / Vasilyev, Nikita / Luciano, Daniel J / Levenson-Palmer, Rose / Richards, Jamie / Marsiglia, William M / Traaseth, Nathaniel J / Belasco, Joel G / Serganov, Alexander

Nucleic acids research

2018 Volume 46, Issue 13, Page(s) 6841–6856

Abstract: Vitally important for controlling gene expression in eukaryotes and prokaryotes, the deprotection of mRNA 5' termini is governed by enzymes whose activity is modulated by interactions with ancillary factors. In Escherichia coli, 5'-end-dependent mRNA ... ...

Abstract	Vitally important for controlling gene expression in eukaryotes and prokaryotes, the deprotection of mRNA 5' termini is governed by enzymes whose activity is modulated by interactions with ancillary factors. In Escherichia coli, 5'-end-dependent mRNA degradation begins with the generation of monophosphorylated 5' termini by the RNA pyrophosphohydrolase RppH, which can be stimulated by DapF, a diaminopimelate epimerase involved in amino acid and cell wall biosynthesis. We have determined crystal structures of RppH-DapF complexes and measured rates of RNA deprotection. These studies show that DapF potentiates RppH activity in two ways, depending on the nature of the substrate. Its stimulatory effect on the reactivity of diphosphorylated RNAs, the predominant natural substrates of RppH, requires a substrate long enough to reach DapF in the complex, while the enhanced reactivity of triphosphorylated RNAs appears to involve DapF-induced changes in RppH itself and likewise increases with substrate length. This study provides a basis for understanding the intricate relationship between cellular metabolism and mRNA decay and reveals striking parallels with the stimulation of decapping activity in eukaryotes.
MeSH term(s)	Acid Anhydride Hydrolases/chemistry ; Acid Anhydride Hydrolases/metabolism ; Allosteric Regulation ; Amino Acid Isomerases/chemistry ; Amino Acid Isomerases/metabolism ; Escherichia coli Proteins/chemistry ; Escherichia coli Proteins/metabolism ; Kinetics ; Models, Molecular ; Protein Binding ; Protein Multimerization ; RNA, Messenger/metabolism
Chemical Substances	Escherichia coli Proteins ; RNA, Messenger ; Acid Anhydride Hydrolases (EC 3.6.-) ; RppH protein, E coli (EC 3.6.1.-) ; Amino Acid Isomerases (EC 5.1.1.-) ; DapF protein, E coli (EC 5.1.1.7) ; diaminopimelate epimerase (EC 5.1.1.7)
Language	English
Publishing date	2018-05-03
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gky327
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