ATP-competitive Inhibitors Modulate the Substrate Binding Cooperativity of a Kinase by Altering Its Conformational Entropy

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2022 Jul 29

PMID 35905186

Authors

Cristina Olivieri

Geoffrey C Li

Yingjie Wang

Manu V S

Caitlin Walker

Jonggul Kim

Carlo Camilloni

Alfonso De Simone

Michele Vendruscolo

David A Bernlohr

Susan S Taylor

Gianluigi Veglia

Affiliations

Soon will be listed here.

Abstract

ATP-competitive inhibitors are currently the largest class of clinically approved drugs for protein kinases. By targeting the ATP-binding pocket, these compounds block the catalytic activity, preventing substrate phosphorylation. A problem with these drugs, however, is that inhibited kinases may still recognize and bind downstream substrates, acting as scaffolds or binding hubs for signaling partners. Here, using protein kinase A as a model system, we show that chemically different ATP-competitive inhibitors modulate the substrate binding cooperativity by tuning the conformational entropy of the kinase and shifting the populations of its conformationally excited states. Since we found that binding cooperativity and conformational entropy of the enzyme are correlated, we propose a new paradigm for the discovery of ATP-competitive inhibitors, which is based on their ability to modulate the allosteric coupling between nucleotide and substrate-binding sites.

Citing Articles

Advances in pyrazolo[1,5-]pyrimidines: synthesis and their role as protein kinase inhibitors in cancer treatment.

Iorkula T, Jude-Kelly Osayawe O, Odogwu D, Ganiyu L, Faderin E, Awoyemi R RSC Adv. 2025; 15(5):3756-3828.

PMID: 39911541 PMC: 11795850. DOI: 10.1039/d4ra07556k.

Role of the αC-β4 loop in protein kinase structure and dynamics.

Wu J, Jonniya N, Hirakis S, Olivieri C, Veglia G, Kornev A Elife. 2024; 12.

PMID: 39630082 PMC: 11616992. DOI: 10.7554/eLife.91980.

Exploring the conformational landscape of protein kinases.

Gough N, Kalodimos C Curr Opin Struct Biol. 2024; 88:102890.

PMID: 39043011 PMC: 11694674. DOI: 10.1016/j.sbi.2024.102890.

The αC-β4 loop controls the allosteric cooperativity between nucleotide and substrate in the catalytic subunit of protein kinase A.

Olivieri C, Wang Y, Walker C, Veliparambil Subrahmanian M, Ha K, Bernlohr D Elife. 2024; 12.

PMID: 38913408 PMC: 11196109. DOI: 10.7554/eLife.91506.

CDK2 and CDK4: Cell Cycle Functions Evolve Distinct, Catalysis-Competent Conformations, Offering Drug Targets.

Zhang W, Liu Y, Jang H, Nussinov R JACS Au. 2024; 4(5):1911-1927.

PMID: 38818077 PMC: 11134382. DOI: 10.1021/jacsau.4c00138.

References

Tzeng S, Kalodimos C . Dynamic activation of an allosteric regulatory protein. Nature. 2009; 462(7271):368-72. DOI: 10.1038/nature08560. View

Foda Z, Shan Y, Kim E, Shaw D, Seeliger M . A dynamically coupled allosteric network underlies binding cooperativity in Src kinase. Nat Commun. 2015; 6:5939. PMC: 4300553. DOI: 10.1038/ncomms6939. View

Lisi G, Manley G, Hendrickson H, Rivalta I, Batista V, Loria J . Dissecting Dynamic Allosteric Pathways Using Chemically Related Small-Molecule Activators. Structure. 2016; 24(7):1155-66. PMC: 4938718. DOI: 10.1016/j.str.2016.04.010. View

Lisi G, Loria J . Solution NMR Spectroscopy for the Study of Enzyme Allostery. Chem Rev. 2016; 116(11):6323-69. PMC: 4937494. DOI: 10.1021/acs.chemrev.5b00541. View

Kim J, Masterson L, Cembran A, Verardi R, Shi L, Gao J . Dysfunctional conformational dynamics of protein kinase A induced by a lethal mutant of phospholamban hinder phosphorylation. Proc Natl Acad Sci U S A. 2015; 112(12):3716-21. PMC: 4378435. DOI: 10.1073/pnas.1502299112. View

Neudecker P, Robustelli P, Cavalli A, Walsh P, Lundstrom P, Zarrine-Afsar A . Structure of an intermediate state in protein folding and aggregation. Science. 2012; 336(6079):362-6. DOI: 10.1126/science.1214203. View

Wang C, Rance M, Palmer 3rd A . Mapping chemical exchange in proteins with MW > 50 kD. J Am Chem Soc. 2004; 125(30):8968-9. DOI: 10.1021/ja035139z. View

Long D, Marshall C, Bouvignies G, Mazhab-Jafari M, Smith M, Ikura M . A comparative CEST NMR study of slow conformational dynamics of small GTPases complexed with GTP and GTP analogues. Angew Chem Int Ed Engl. 2013; 52(41):10771-4. DOI: 10.1002/anie.201305434. View

Caro J, Harpole K, Kasinath V, Lim J, Granja J, Valentine K . Entropy in molecular recognition by proteins. Proc Natl Acad Sci U S A. 2017; 114(25):6563-6568. PMC: 5488930. DOI: 10.1073/pnas.1621154114. View

10.

Kleckner I, Foster M . GUARDD: user-friendly MATLAB software for rigorous analysis of CPMG RD NMR data. J Biomol NMR. 2011; 52(1):11-22. PMC: 3593345. DOI: 10.1007/s10858-011-9589-y. View

11.

Manning G, Whyte D, Martinez R, Hunter T, Sudarsanam S . The protein kinase complement of the human genome. Science. 2002; 298(5600):1912-34. DOI: 10.1126/science.1075762. View

12.

Wang Y, V S M, Kim J, Li G, Ahuja L, Aoto P . Globally correlated conformational entropy underlies positive and negative cooperativity in a kinase's enzymatic cycle. Nat Commun. 2019; 10(1):799. PMC: 6379427. DOI: 10.1038/s41467-019-08655-7. View

13.

Selvaratnam R, Chowdhury S, VanSchouwen B, Melacini G . Mapping allostery through the covariance analysis of NMR chemical shifts. Proc Natl Acad Sci U S A. 2011; 108(15):6133-8. PMC: 3076865. DOI: 10.1073/pnas.1017311108. View

14.

Stetz M, Caro J, Kotaru S, Yao X, Marques B, Valentine K . Characterization of Internal Protein Dynamics and Conformational Entropy by NMR Relaxation. Methods Enzymol. 2019; 615:237-284. PMC: 6364297. DOI: 10.1016/bs.mie.2018.09.010. View

15.

Kumar G, Clarkson M, Kunze M, Granata D, Wand A, Lindorff-Larsen K . Dynamic activation and regulation of the mitogen-activated protein kinase p38. Proc Natl Acad Sci U S A. 2018; 115(18):4655-4660. PMC: 5939092. DOI: 10.1073/pnas.1721441115. View

16.

Narayana N, Diller T, Koide K, Bunnage M, Nicolaou K, Brunton L . Crystal structure of the potent natural product inhibitor balanol in complex with the catalytic subunit of cAMP-dependent protein kinase. Biochemistry. 1999; 38(8):2367-76. DOI: 10.1021/bi9820659. View

17.

Pegram L, Liddle J, Xiao Y, Hoh M, Rudolph J, Iverson D . Activation loop dynamics are controlled by conformation-selective inhibitors of ERK2. Proc Natl Acad Sci U S A. 2019; 116(31):15463-15468. PMC: 6681744. DOI: 10.1073/pnas.1906824116. View

18.

Lee W, Tonelli M, Markley J . NMRFAM-SPARKY: enhanced software for biomolecular NMR spectroscopy. Bioinformatics. 2014; 31(8):1325-7. PMC: 4393527. DOI: 10.1093/bioinformatics/btu830. View

19.

Korzhnev D, Salvatella X, Vendruscolo M, Di Nardo A, Davidson A, Dobson C . Low-populated folding intermediates of Fyn SH3 characterized by relaxation dispersion NMR. Nature. 2004; 430(6999):586-90. DOI: 10.1038/nature02655. View

20.

Hemmer W, McGlone M, Taylor S . Recombinant strategies for rapid purification of catalytic subunits of cAMP-dependent protein kinase. Anal Biochem. 1997; 245(2):115-22. DOI: 10.1006/abio.1996.9952. View