Crystal Structure of the P38α-MAPKAP Kinase 2 Heterodimer

Haar, Ernst ter; Prabakhar, Prakash; Liu, Xun; Lepre, Christopher A.

doi:10.1074/jbc.m611165200

Cited by 96 publications

(54 citation statements)

References 40 publications

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“…Since the submission of this manuscript, the structure of a similar complex solved at the significantly lower resolution of 4Å has been reported online (51).…”

Section: Methods P38␣mentioning

confidence: 99%

Molecular basis of MAPK-activated protein kinase 2:p38 assembly

White

Pargellis

Studts

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

106

109

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p38 MAPK and MAPK-activated protein kinase 2 (MK2) are key components of signaling pathways leading to many cellular responses, notably the proinflammatory cytokine production. The physical association of p38␣ isoform and MK2 is believed to be physiologically important for this signaling. We report the 2.7-Å resolution crystal structure of the unphosphorylated complex between p38␣ and MK2. These protein kinases bind ''head-to-head,'' present their respective active sites on approximately the same side of the heterodimer, and form extensive intermolecular interactions. Among these interactions, the MK2 Ile-366 -Ala-390, which includes the bipartite nuclear localization signal, binds to the p38␣-docking region. This binding supports the involvement of noncatalytic regions to the tight binding of the MK2:p38␣ binary assembly. The MK2 residues 345-365, containing the nuclear export signal, block access to the p38␣ active site. Some regulatory phosphorylation regions of both protein kinases engage in multiple interactions with one another in this complex. This structure gives new insights into the regulation of the protein kinases p38␣ and MK2, aids in the better understanding of their known cellular and biochemical studies, and provides a basis for understanding other regulatory protein-protein interactions involving signal transduction proteins.X-ray structure T he MAPK has been directly associated with proinflammatory cytokine production. Inhibition of p38␣ (and its homolog, p38␤) by inhibitors such as SB203580 and BIRB 796, reduces LPS-induced production of proinflammatory cytokines, including TNF␣ and IL-1, that are implicated in the etiology of chronic inflammation (1-5). Recent genetic evidence suggests that p38␣, not p38␤, is the major p38 isoform involved in the LPS-induced immune response (6). Embryonic stem cells derived from mice that lack the p38␣ function exhibit impaired IL-1 signaling (7). Biological therapies directed against inflammatory cytokines, e.g., anti-TNF␣ and anti-IL-1␤, have also proven effective at ameliorating the symptoms of inflammatory diseases such as arthritis and psoriasis (not anti-IL-1␤-mediated) (8-11).MAPK-activated protein kinase-2 (MK2), the primary substrate of p38␣, is also a key participant in modulating proinflammatory cytokine production (12, 13). MK2 knockout mice (MK2 Ϫ/Ϫ ) challenged with LPS produce significantly less TNF␣, IL-6, IFN␥, and IL-1 than LPS-stimulated wild-type mice (13). MK2Ϫ/Ϫ mice are also resistant to collagen-induced arthritis (14). The transfection of cultured keratinocytes with MK2-specific small interfering RNA led to a significant decrease in MK2 protein expression and a subsequent, significant reduction in the production of TNF␣, . The catalytic activity of MK2 has further been shown to be necessary for TNF␣ production (16). Taken together, these data suggest that the inhibition of the p38␣ pathway, particularly MK2, is desirable for the potential treatment of chronic inflammation.In resting cells, p38␣ forms a physiological complex with MK2, w...

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“…Since the submission of this manuscript, the structure of a similar complex solved at the significantly lower resolution of 4Å has been reported online (51).…”

Section: Methods P38␣mentioning

confidence: 99%

Molecular basis of MAPK-activated protein kinase 2:p38 assembly

White

Pargellis

Studts

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

106

109

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“…Another crystal structure of the p38-MK2 heterodimeric complex was solved at 4.0 Å resolution (PDB entry 2onl), that represented the first example of full length kinase crystallized in a complex. 31 …”

Section: Structural and Functional Features Of Mk2mentioning

confidence: 99%

Targeting Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MAPKAPK2, MK2): Medicinal Chemistry Efforts To Lead Small Molecule Inhibitors to Clinical Trials

2015

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The p38/MAPK-activated kinase 2 (MK2) pathway is involved in a series of pathological conditions (inflammation diseases and metastasis) and in the resistance mechanism to antitumor agents. None of the p38 inhibitors entered advanced clinical trials because of their unwanted systemic side effects. For this reason, MK2 was identified as an alternative target to block the pathway, but avoiding the side effects of p38 inhibition. However, ATP-competitive MK2 inhibitors suffered from low solubility, poor cell permeability, and scarce kinase selectivity. Fortunately, non-ATP-competitive inhibitors of MK2 have been already discovered that allowed circumventing the selectivity issue. These compounds showed the additional advantage to be effective at lower concentrations in comparison to the ATP-competitive inhibitors. Therefore, although the significant difficulties encountered during the development of these inhibitors, MK2 is still considered as an attractive target to treat inflammation and related diseases, to prevent tumor metastasis, and to increase tumor sensitivity to chemotherapeutics.

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“…Crystal structures with PDB codes 2OZA [10] and 2ONL [11] may constitute representative structures of this heterodimer present in the nucleus. (ii) Alternatively p38α can interact with MKK3 or MKK6 (iii) to be phosphorylated by the action of them.…”

Section: Introductionmentioning

confidence: 99%

Identification of a Novel Inhibitory Allosteric Site in p38α

Gómez-Gutiérrez

Campos²,

Vega³

et al. 2016

PLoS ONE

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In the present study, we report the discovery of a novel allosteric inhibitory site for p38α, a subclass of the mitogen-activated protein kinases (MAPK) family. The putative site was discovered after inspection of the crystallographic structure of the p38α-MK2 complex. MK2 (MAPK-activated protein kinase 2) is an interesting protein playing a dual role as modulator and substrate of p38α. This intriguing behavior is due to the ability of the two proteins to form distinctive heterodimers when p38α is phosphorylated or not. We hypothesized that the regulatory action of MK2 is due to its capability to keep p38α in an inactive conformation and consequently, we investigated the atomic structure of the p38α-MK2 complex to understand such regulatory behavior at the molecular level. After inspection of the complex structure, two peptides designed from the MK2 regulatory loop in contact with p38α with sequences Tyr1-Ser2-Asn3-His4-Gly5-Leu6 (peptide-1) and [Phe0]-peptide-1 (peptide-2) in their zwitterionic form were investigated for their phosphorylation inhibitory capability in vitro. Since both peptides exhibited inhibitory capability of the p38α kinase mediated phosphorylation of MEF2A, in a subsequent step we pursued the discovery of small molecule peptidomimetics. For this purpose we characterized in detail the peptide-p38α interaction using molecular dynamics simulations, leading to the definition of a pharmacophore for the peptide-protein interaction. This hypothesis was used as query for a in silico screening, leading to the discovery of a fused ring compound with micromolar inhibitory activity. Site-directed mutagenesis studies support that the compound binds to the putative novel allosteric site in p38α.

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Crystal Structure of the P38α-MAPKAP Kinase 2 Heterodimer

Cited by 96 publications

References 40 publications

Molecular basis of MAPK-activated protein kinase 2:p38 assembly

Molecular basis of MAPK-activated protein kinase 2:p38 assembly

Targeting Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MAPKAPK2, MK2): Medicinal Chemistry Efforts To Lead Small Molecule Inhibitors to Clinical Trials

Identification of a Novel Inhibitory Allosteric Site in p38α

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