The extracellular signal-regulated protein kinases, ERK1/2, are key components of the MAP kinase signaling pathway controlling cell proliferation, survival, morphology, and migration (Lavoie et al., 2020; Roskoski, 2012; Plotnikov et al., 2011). Due to the prevalence of oncogenic mutations in Ras, RAF, and MEK, components of this pathway have been targeted for the development of successful anti-cancer therapies (Halle and Johnson, 2021; Tangella et al., 2021; Canon et al., 2019; Ryan et al., 2020). Although inhibitors targeting ERK1/2 have not advanced to clinical use, clinical trials are ongoing for several, including ulixertinib/BVD523 (Biomed Valley Diagnostics), ravoxertinib/GDC0994 (Genentech), and tizakertib/ATG017/AZD0364 (Antengene), for the treatment of cancers with activating mutations in KRAS, BRAF, NRAS, MEK1/2, and ERK1/2 (Grierson et al., 2023; Goodwin et al., 2023; Wu et al., 2021; Varga et al., 2020; Kong et al., 2023; Chen et al., 2021). Importantly, reversible ATP-competitive inhibitors targeting ERK1/2 have been shown to be effective in cancer cells and tumors with acquired resistance to BRAF and MEK inhibitors (Ryan et al., 2015; Morris et al., 2013; Hatzivassiliou et al., 2012; Roskoski, 2019; Pan et al., 2022). Therefore, future anticancer drug development would benefit from a more complete understanding of the properties of ERK inhibitors.

Many protein kinases undergo relatively large conformational changes when they switch from inactive to active states. Such changes lead to the repositioning of conserved active site residues, including a Lys-Glu salt bridge in the N-terminal lobe between strand β3 and helix αC that hydrogen bonds with nucleotide phosphate, an Asp residue in the DFG motif that coordinates Mg²⁺, and an Asp in the HRD motif that catalyzes base-assisted phosphoryl transfer to the substrate hydroxyl acceptor (Taylor et al., 2019; Amatya et al., 2019). By contrast, ERK2 is unusual in that only small conformational changes occur within the active site between the inactive, unphosphorylated (0P) and the active, dual phosphorylated (2P) forms of the kinase (Figure 1). X-ray structures show that dual phosphorylation of ERK2 at T183 and Y185 remodels the activation loop by forming phosphate salt bridges with several Arg residues (Zhang et al., 1994; Canagarajah et al., 1997). This accommodates the S/T-P recognition motif common to ERK substrates and exposes a pocket for binding a hydrophobic docking motif found in substrates, scaffolds, and other effectors (Lee et al., 2004). But within the ATP binding site, the conserved residues that form the K52-E69 salt bridge, the DFG metal binding site (D165), and the HRD catalytic base (D147) are largely overlapping (Figure 1C). Thus, the changes in the active site that accompany ERK2 activation are small and difficult to discern crystallographically.

Figure 1

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Solution measurements revealed that the activation of ERK2 is accompanied by changes in protein dynamics. NMR Carr-Purcell-Meiboom-Gill (CPMG) relaxation dispersion measurements showed that dual phosphorylation results in a global exchange behavior that can be modeled by two conformational states, named ‘R’ and ‘L,’ which exchange on a millisecond timescale (Xiao et al., 2014; Xiao et al., 2015; Iverson et al., 2020). Thus, 2P-ERK2 can be characterized by the interconversion of at least two conformers. Whereas the L-state resembles that seen with 0P-ERK2, the R-state appears only in 2P-ERK2, where it exchanges with an R:L population ratio of 80:20 at 25 °C. Crystal structures of nucleotide-bound kinase show significant differences between 0P- and 2P-ERK2. In 2P-ERK2, the ATP analog, AMP-PNP, is positioned close to the catalytic base and in-line for nucleophilic attack on the Pγ phosphate (Pegram et al., 2019; Lechtenberg et al., 2017). By contrast, ATP bound to 0P-ERK2 is markedly distorted, moving Pγ away from the base by more than 6 Å (Zhang et al., 2012; Smorodinsky-Atias et al., 2016). Thus, despite the structural similarity between the apoenzyme forms, 2P-ERK2 promotes ATP binding interactions that are more productive for catalytic function. The unique appearance of the R-state in 2P-ERK2 has been proposed to confer the ability to form a Michaelis complex poised for phosphoryl transfer, while L may represent a state that promotes ADP product release (Pegram et al., 2019).

Interestingly, ATP competitive inhibitors of ERK show properties of conformation selection, where ligand binding traps conformational states in 2P-ERK2 that normally undergo reversible exchange in the apoenzyme. Binding of the inhibitor, Vertex-11e (VTX11e), to 2P-ERK2 shifts the L↔R equilibrium completely to the R-state, while the inhibitor SCH772984 shifts the equilibrium completely to the L-state (Rudolph et al., 2015; Pegram et al., 2019). Conformation selection is absent in the inhibitor, GDC0994, where R and L retain a population ratio similar to that seen in the apoenzyme (Pegram et al., 2019). This selective recognition could explain why the binding of VTX11e is stronger to 2P-ERK2 than 0P-ERK2 (Rudolph et al., 2015). In contrast, GDC0994 and SCH772984 bind both active and inactive kinase forms with equal affinity (Pegram et al., 2019; Ward et al., 2019).

HDX-MS also reveals differences between VTX11e, GDC0994, and SCH772984 in their ability to induce perturbations at the P+1 segment (Pegram et al., 2019). P+1 is distal to the kinase active site, and together with the activation loop forms part of the interface for substrate and effector binding. This suggests that R↔L conformational shifts within the active site can propagate out to the activation loop and surrounding regions. NMR-CPMG measurements confirm this, by showing that residues in the activation loop participate in the same global exchange motion as residues surrounding the active site (Iverson et al., 2020). Therefore, solution measurements of conformation selective inhibitors reveal allosteric coupling between the active site and distal regions around the activation loop.

A consequence of this behavior is that conformation-selective inhibitors can alter the interactions of ERK2 with other proteins. For example, the binding of VTX11e partially inhibits the rate of dephosphorylation at the activation loop by the MAP kinase phosphatase, MKP3/DUSP6, while SCH772984 enhances this rate (Pegram et al., 2019). The features of VTX11e controlling its property of R-state selection are unknown. An attempt to address this compared crystal structures of complexes formed between 2P-ERK2 and VTX11e (100% R), GDC0994 (80% R), or SCHCPD336, a close analog of SCH772984 (0% R) (Pegram et al., 2019; Chaikuad et al., 2014; Blake et al., 2016). But the results were inconclusive. Binding of SCHCPD336 disrupted Gly loop and helix αC interactions leading to a disordered activation loop, suggesting that the L-state might communicate N-lobe conformational changes to the activation loop dynamics. In contrast, VTX11e and GDC0994 formed similar close contacts with active site residues with no major distortions in the ATP pocket. Given the limited set of compounds with small structural differences, it was difficult to identify features of binding that could explain why VTX11e is selective for the R-state but GDC0994 is not.

Here, we survey a panel of small molecules with varying chemistries, using HDX-MS and NMR to classify their properties of conformation selection. Of the 19 inhibitors examined, 14 behave in a similar manner to VTX11e, with conformational selection for the R-state. These include 13 novel inhibitors and ulixertinib/BVD523, a promising ERK inhibitor with blood-brain barrier permeability (Sullivan et al., 2018; Yu et al., 2022; Sigaud et al., 2023). Four inhibitors resemble GDC0994 in allowing R↔L exchange with populations comparable to apoenzyme, and one allows exchange but partially shifts the equilibrium toward the R-state. NMR chemical shifts reveal perturbations unique to R-state inhibitors located in the P+1 segment and helix αL16, and remote from the inner-sphere region of ligand contact. Co-crystal structures of R-state selective inhibitors complexed with ERK2 show small but systematic conformational shifts in the Gly loop, helix αC, and helix αL16, in which the Gly loop moves closer to the DFG segment, while helicesαC and αL16 shift outwards. This movement rotates the N- and C-lobes into a more closed configuration and moves the K52-E69 salt bridge closer to the conserved DFG motif. Such small but systematic conformational shifts suggest a working model for R-state selection, involving movements of the N-lobe that favor a more compact active site with allosteric coupling to the activation loop.

ERK inhibitors are promising therapeutic targets for cancers harboring oncogenic BRAF or RAS with acquired resistance to RAF and MEK inhibitors (Ryan et al., 2015; Morris et al., 2013; Hatzivassiliou et al., 2012; Roskoski, 2019; Pan et al., 2022). A feature of ERK2 activation that is somewhat unique among protein kinases is its global exchange behavior, involving millisecond interconversion between at least two states in its active, dual phosphorylated form. In this study, we present new ATP-competitive inhibitors of ERK1/2 that, despite their chemical divergence from VTX11e and BVD523, nevertheless share properties of R-state selection. They display sensitivity to the conformational differences between the R and L-states and the ability to induce long-distance perturbations at the P+1 segment and helix αL16. Crystallographic structures show correlations between the property of R-state selection and small but systematic shifts in the N-lobe that move helices αC and αL16 in the direction of the activation loop. This appears to be facilitated by movements of strands β1-β2-β3 coupled to helix αC. The findings reveal the importance of contacts between strand β3 and helix αC via the positioning of the K52-E69 salt bridge in ERK2, as well as the unique π−π contacts between Tyr residues in the Gly loop and helix αC, in guiding conformation selection for the R-state. By contrast, the binding of SCH772984 disrupts β3-αC contacts in ERK2 (Chaikuad et al., 2014), which may explain why this inhibitor favors the L-state (Pegram et al., 2019).

Unlike many other kinases, activation of ERK leads to relatively small structural changes within the active site. In 0P-ERK2, the N and C lobes are held apart by the backbone atoms of G167 in the DFG motif, which interdigitates with R65 and Q64 in helix αC (Zhang et al., 1994). This domain separation has been proposed to account for the low activity of unphosphorylated ERK2. Following phosphorylation, residue R65 rotates along with helix αC in the direction of the activation loop and pT183, partially relieving the barrier formed by G167. The resulting domain rotation between N- and C-lobes is only 5 degrees, but it brings K52 closer to D165 by 1.5 Å. The small magnitude of these changes are in part due to structural constraints unique to ERK2. Here, residues in the C-terminal L16 segment extending from the C-lobe to the N-lobe (e.g. Y316, D319, E320, F327, and M331) form close contacts with residues in helices αC and αE and the activation loop (Figure 11A). They culminate in helix αL16, where residues I345 and F346 fill a hydrophobic pocket formed by residues in helix αC and the β4-β5 loop (Figure 11B). This placement of helix αL16 aligns structurally with hydrophobic motif (HM) sequences at the C-termini of PKA and members of the AGC kinase subfamily (Taylor et al., 2022; Kannan et al., 2007; Baffi and Newton, 2022), as well as cyclins complexed with CDK (Tatum and Endicott, 2020). Thus helix αL16 coincides with regions in other kinases also involved in long-distance allostery.

Figure 11 with 1 supplement see all

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Many of the key [methyl-¹³C,¹H]-ILV probes that report global exchange behavior in ERK2 are part of the extensive network of hydrophobic residues connecting these substructures. Thus, the side chain of I345 fills a deep hydrophobic pocket formed by T66, L67, and I70 in helix αC, F57 in the β3-αC loop, V99 in strand β5, and M96 in loop β4-β5 (Figure 11B). This network also includes contacts formed by αL16 residue F346 with R89, I93, and M96 in the β4-β5 loop, and F352 with L74, I84, and I87 in αC and β4. Furthermore, side chains from F327 and M331 in L16 fill a hydrophobic pocket formed by I72, R75, and F76 in helix αC, V143 in the αE-β6 loop, and V171 in the activation loop (Figure 11A). In turn, I72 and F76 form hydrophobic contacts with L73 in helix αC, I138 in helix αE, and F166 in the DFG motif. Thus, αL16 and L16 contact the N-lobe via a hydrophobic network that merges with the R-spine (L73, I84, F166). Such extensive packing interactions may help to constrain ERK2, preventing the backbone rotational movements needed to allow a DFG-out configuration (Vijayan et al., 2015), which is never observed in the wild-type kinase. Conceivably, the conformations involved in R↔L global exchange could reflect systematic movements within this network, which propagate to produce the chemical shift perturbations observed in I345. Although such conformational shifts are small, the coupling between movements of the Gly loop and helices αC and αL16 are complementary to the N-lobe movements seen upon ERK2 phosphorylation. It is remarkable that inhibitors that share similar binding interactions and active site contacts are sensitive to such small conformational differences.

This study shows how HDX-MS and NMR are sensitive to slight perturbations within the active site that lead to significant long-distance responses at the activation loop and P+1 segment. Large structural rearrangements around the activation loop were not obvious in the X-ray structures of 2P-ERK2 complexed with GDC0994, VTX11e, or inhibitors #8 and #16. However, evidence that these measurements truly report conformational changes around pT183 and pY185 was supported by the ability of VTX11e to inhibit their rate of dephosphorylation by MAP kinase phosphatase (MKP3/DUSP6, Pegram et al., 2019). This demonstrates the protection of the activation loop by VTX11e binding. Conceivably, the conformation of the activation loop in solution may be more variable than in crystal structures of 2P-ERK2, in part due to lattice restraints. This is suggested by the extensive lattice contacts with the activation loop and P+1 segment in complexes formed by VTX11e, GDC0994, and inhibitors #8 and #16 (Figure 11—figure supplement 1). In fact, crystal contacts are positioned in a manner that might influence the activation loop in most X-ray structures of ERK2 (Pegram et al., 2023). This highlights the need for solution measurements to more fully understand allosteric regulation in ERK2.

Recently, we conducted extended molecular dynamics simulations (225 μs) starting from the X-ray structure of 2P-ERK2 (PDBID: 2ERK) (Pegram et al., 2023). The results showed unexpected flexibility of the activation loop, which deviated from the X-ray fold in all trajectories and was able to adopt multiple long-lived conformational states with RMSF ≤1.2 Å and lasting for more than 5 μs. Each state appeared only after 1–5 μs, perhaps due to biases introduced by lattice contacts in the starting model. Importantly, the states varied significantly in the contacts formed between the activation loop, L16, and the P+1 segment. These variable activation loop conformations were associated with differential dynamics within the active site, supporting allosteric coupling between these regions. Interestingly, in one of the novel states, the Arg salt bridges formed between pY185 and the P+1 segment were broken, allowing the phosphorylated side chain to move away and form a new salt bridge with helix αC. This reorganization resembled that observed in a co-crystal structure of 2P-ERK2 and the adaptor protein, PEA15 (Mace et al., 2013). The results suggest that distinct conformational states of the activation loop appear thermally accessible and likely to exist in solution. We speculate that they may function to accommodate variable binding modes for substrates and effectors. To the extent this is true, the coupling between the active site and activation loop in ERK2 might allow conformation selective inhibitors to control the binding of substrates and regulatory effectors. Similarly, allosteric properties in PKA allow different ATP-competitive inhibitors to vary the cooperativity of substrate binding (Olivieri et al., 2022).

Indeed, remote conformational changes induced by conformation selective inhibitors have been shown to alter noncatalytic scaffolding functions of protein kinases via interactions with regulatory enzymes (Agudo-Ibáñez et al., 2023; Leroux and Biondi, 2020; Fang et al., 2020; Sonti et al., 2018; Joseph et al., 2022). In fact, an intriguing recent study demonstrates that ubiquitination and degradation of 2P-ERK2 can be enhanced by BVD523, suggesting that conformation selective inhibitors may act as ‘kinase degraders’ that preferentially target the activated kinase (Balmanno et al., 2023). Other noncatalytic functions of ERK2 include the activation of topoisomerase IIα and poly-ADP ribose polymerase via direct binding of the phosphorylated kinase (Shapiro et al., 1999; Cohen-Armon et al., 2007). Preferential binding of DNA to 2P-ERK2 has also been shown to function in ERK1/2 binding to chromatin DNA, with a proposed regulation of transcription through phosphorylation-independent mechanisms (Hu et al., 2009; Lawrence et al., 2008; McReynolds et al., 2016; Tee et al., 2014). Thus, the ability of R-state inhibitors to control solution conformations of the activation loop may influence emerging noncatalytic functions of ERK.

In summary, the case of ERK2 illustrates how very small conformational changes in protein kinases can lead to considerable effects on activity and inhibition. Correspondingly, small variations between inhibitors which otherwise share similar binding interactions and active site contacts, differentially control long-distance allosteric effects that induce conformational changes at the activation loop. Such differences may be important for cellular responses, by altering the conformation of ERK at a key interface for substate and effector recognition. This highlights the importance of understanding the properties of conformation selection in ERK, and how these unique features of ERK regulation impact inhibitor design. The elements of protein architecture that enable small active site movements to yield large effects in distal regions remain an important and exciting feature of MAP kinases to explore in future investigations.

Crystallography data have been deposited in the PDB under accession codes 8U8J and 8U8K. Data generated from HDX experiments, including Supplementary Dataset S1, coverage maps, and representative raw spectra have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository Perez-Riverol et al., 2022, with the dataset identifier PXD048311. Data generated from NMR experiments have been deposited in BMRbig under accession code BMRbig96.

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Author details

1. Jake W Anderson

   Department of Biochemistry, University of Colorado, Boulder, United States

   Present address

   Department of Biochemistry, Oxford University, Oxford, United Kingdom

   Contribution

   Conceptualization, Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-8757-7408

2. David Vaisar

   Department of Biochemistry, University of Colorado, Boulder, United States

   Contribution

   Data curation, Formal analysis, Investigation, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

3. David N Jones

   Department of Pharmacology, University of Colorado Anschutz Medical Center, Boulder, United States

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Validation, Investigation, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

4. Laurel M Pegram

   Department of Biochemistry, University of Colorado, Boulder, United States

   Present address

   Loxo Oncology, Louisville, United States

   Contribution

   Conceptualization, Validation, Investigation, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

5. Guy P Vigers

   ArrayBioPharma, Inc., Boulder, United States

   Present address

   Allium Consulting LLC, Boulder, United States

   Contribution

   Data curation, Formal analysis, Validation, Methodology, Writing – review and editing

   Competing interests

   Guy Vigers is Structural Biology Consultant at Allium Consulting LLC

6. Huifen Chen

   Genentech, Inc., South San Francisco, United States

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Validation, Investigation, Methodology, Writing – review and editing

   Competing interests

   Dr. Huifen Chen is Distinguished Scientist at Genentech, Inc

7. John G Moffat

   Genentech, Inc., South San Francisco, United States

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Validation, Investigation, Methodology, Writing – review and editing

   Competing interests

   Dr. John Moffat is Distinguished Scientist at Genentech, Inc

8. Natalie G Ahn

   Department of Biochemistry, University of Colorado, Boulder, United States

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing – original draft, Project administration

   For correspondence

   natalie.ahn@colorado.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-2690-2630

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