Conformational control and regulation of the pseudokinase KSR via small molecule binding interactions.
Activity-based probes
Crystallization
Interfacial sites
KSR
MEK
Molecular glues
Orthosteric site
RAF
SBDD
Target engagement
Journal
Methods in enzymology
ISSN: 1557-7988
Titre abrégé: Methods Enzymol
Pays: United States
ID NLM: 0212271
Informations de publication
Date de publication:
2022
2022
Historique:
entrez:
7
5
2022
pubmed:
8
5
2022
medline:
11
5
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35525547
pii: S0076-6879(22)00130-6
doi: 10.1016/bs.mie.2022.03.039
pmc: PMC9150438
mid: NIHMS1805519
pii:
doi:
Substances chimiques
Protein Kinases
EC 2.7.-
Protein Serine-Threonine Kinases
EC 2.7.11.1
Proto-Oncogene Proteins c-raf
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
365-402Subventions
Organisme : NCI NIH HHS
ID : K00 CA212474
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA258736
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA078207
Pays : United States
Organisme : NIA NIH HHS
ID : R56 AG066712
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA227636
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA256480
Pays : United States
Informations de copyright
Copyright © 2022 Elsevier Inc. All rights reserved.
Références
Cancer Cell. 2014 May 12;25(5):697-710
pubmed: 24746704
Genes Dev. 1996 Nov 1;10(21):2684-95
pubmed: 8946910
Biochemistry. 2020 Oct 20;59(41):3982-3992
pubmed: 32970425
Proc Natl Acad Sci U S A. 2011 Apr 12;108(15):6067-72
pubmed: 21441104
Biochemistry. 2021 Feb 2;60(4):289-302
pubmed: 33440120
Mol Cell Biol. 2002 May;22(9):3035-45
pubmed: 11940661
Methods Enzymol. 2014;536:149-63
pubmed: 24423274
Curr Biol. 1997 May 1;7(5):294-300
pubmed: 9115393
Cell. 1995 Dec 15;83(6):879-88
pubmed: 8521512
Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6213-7
pubmed: 8327501
Cell. 1997 Apr 4;89(1):63-72
pubmed: 9094715
Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):12792-6
pubmed: 9371754
Nat Struct Mol Biol. 2020 Feb;27(2):134-141
pubmed: 31988522
Nature. 2011 Apr 21;472(7343):366-9
pubmed: 21441910
Nat Rev Mol Cell Biol. 2015 May;16(5):281-98
pubmed: 25907612
Protein Sci. 2021 Aug;30(8):1535-1553
pubmed: 34008902
Mol Cell. 2001 Nov;8(5):983-93
pubmed: 11741534
Nature. 1993 Jul 22;364(6435):308-13
pubmed: 8332187
Nat Commun. 2021 Feb 10;12(1):920
pubmed: 33568647
Biochemistry. 2009 Mar 31;48(12):2661-74
pubmed: 19161339
Cell Metab. 2009 Nov;10(5):366-78
pubmed: 19883615
Nature. 2016 Sep 1;537(7618):112-116
pubmed: 27556948
J Mol Biol. 2005 Sep 2;351(5):1110-22
pubmed: 16054648
Mol Cell Biol. 2006 Mar;26(6):2202-14
pubmed: 16507997
Sci Signal. 2012 Dec 18;5(255):ra94
pubmed: 23250398
Cancer Cell. 2014 Sep 8;26(3):402-413
pubmed: 25155755
Nat Rev Drug Discov. 2016 Feb;15(2):87-95
pubmed: 26678621
Nature. 1995 Jun 15;375(6532):554-60
pubmed: 7791872
J Med Chem. 2019 Dec 12;62(23):10897-10911
pubmed: 31730343
Curr Opin Chem Biol. 2010 Aug;14(4):467-74
pubmed: 20663707
Nature. 2019 Nov;575(7783):545-550
pubmed: 31581174
Cancer Res. 2003 Jul 15;63(14):4232-8
pubmed: 12874031
J Biol Chem. 1995 Feb 17;270(7):2901-5
pubmed: 7852367
PLoS One. 2018 Mar 29;13(3):e0194998
pubmed: 29596465
Proc Natl Acad Sci U S A. 2021 Sep 7;118(36):
pubmed: 34470822
Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):442-6
pubmed: 8421674
Cell. 2013 Aug 29;154(5):1036-1046
pubmed: 23993095
Cell. 1995 Dec 15;83(6):903-13
pubmed: 8521514
Biochemistry. 1996 May 7;35(18):5641-6
pubmed: 8639522
J Cell Sci. 2001 May;114(Pt 9):1609-12
pubmed: 11309192
Nat Chem Biol. 2020 Nov;16(11):1170-1178
pubmed: 32778845
Cell Chem Biol. 2018 Feb 15;25(2):206-214.e11
pubmed: 29174542
Nature. 2018 Feb 22;554(7693):549-553
pubmed: 29433126
Nat Commun. 2021 Feb 19;12(1):1176
pubmed: 33608534
Cancer Res. 2001 May 1;61(9):3595-8
pubmed: 11325826
Methods Mol Biol. 2019;1888:45-71
pubmed: 30519940
J Biol Chem. 1995 Apr 28;270(17):9809-12
pubmed: 7730360
Acta Crystallogr D Biol Crystallogr. 2012 Apr;68(Pt 4):352-67
pubmed: 22505256
Mol Cell Biol. 1999 Jan;19(1):229-40
pubmed: 9858547
Genetics. 1996 May;143(1):315-29
pubmed: 8722784
Cancer Discov. 2019 Mar;9(3):329-341
pubmed: 30770389
Nature. 2020 Dec;588(7838):509-514
pubmed: 32927473
Cell. 2004 Mar 19;116(6):855-67
pubmed: 15035987
Nature. 2009 Sep 24;461(7263):542-5
pubmed: 19727074
Nat Struct Mol Biol. 2015 Jan;22(1):37-43
pubmed: 25437913
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):125-32
pubmed: 20124692
Genes Dev. 2002 Feb 15;16(4):427-38
pubmed: 11850406
Science. 2019 Oct 4;366(6461):109-115
pubmed: 31604311
Chem Biol. 2011 Jun 24;18(6):699-710
pubmed: 21700206
Nat Struct Mol Biol. 2021 Oct;28(10):847-857
pubmed: 34625747
Mol Cell Biol. 1999 Aug;19(8):5523-34
pubmed: 10409742
Cell. 1995 Dec 15;83(6):889-901
pubmed: 8521513
Curr Opin Cell Biol. 2000 Apr;12(2):211-6
pubmed: 10712921
Cancer Res. 2013 Jul 1;73(13):4050-4060
pubmed: 23667175
Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9214-9
pubmed: 9689060
J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674
pubmed: 19461840
Biochemistry. 2007 Jan 16;46(2):350-8
pubmed: 17209545
Cell. 2013 Nov 7;155(4):765-77
pubmed: 24209692
Curr Opin Struct Biol. 2021 Dec;71:223-231
pubmed: 34454301