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Crystal structure of the MAP kinase binding domain and the catalytic domain of human MKP5.

Tao X, Tong L
Protein Sci 16 880-6 (2007)
Cited: 19 times
EuropePMC logo PMID: 17400920

Abstract

MAP kinase phosphatases (MKPs) have crucial roles in regulating the signaling activity of MAP kinases and are potential targets for drug discovery against human diseases. These enzymes contain a catalytic domain (CD) as well as a binding domain (BD) that help recognize the target MAP kinase. We report here the crystal structures at up to 2.2 A resolution of the BD and CD of human MKP5 and compare them to the known structures from other MKPs. Dramatic structural differences are observed between the BD of MKP5 and that of MKP3 determined previously by NMR. In particular, the cluster of positively charged residues that is important for MAP kinase binding is located in completely different positions in the two structures, with a distance of 25 A between them. Moreover, this cluster is alpha-helical in MKP5, while it forms a loop followed by a beta-strand in MKP3. These large structural differences could be associated with the distinct substrate preferences of these phosphatases, but further studies are needed to confirm this. The CD of MKP5 is observed in an active conformation, and two loops in the active site have backbone shifts of up to 5 A relative to the inactive CDs from other MKPs.

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  2. The family-wide structure and function of human dual-specificity protein phosphatases. Jeong DG, Wei CH, Ku B, Jeon TJ, Chien PN, Kim JK, Park SY, Hwang HS, Ryu SY, Park H, Kim DS, Kim SJ, Ryu SE. Acta Crystallogr. D Biol. Crystallogr. 70 421-435 (2014)
  3. A conserved motif in JNK/p38-specific MAPK phosphatases as a determinant for JNK1 recognition and inactivation. Liu X, Zhang CS, Lu C, Lin SC, Wu JW, Wang ZX. Nat Commun 7 10879 (2016)
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  5. Regulation of Inflammatory Cytokine Production by MKP-5 in Macrophages. Hömmö T, Pesu M, Moilanen E, Korhonen R. Basic Clin. Pharmacol. Toxicol. 117 96-104 (2015)
  6. An allosteric site on MKP5 reveals a strategy for small-molecule inhibition. Gannam ZTK, Min K, Shillingford SR, Zhang L, Herrington J, Abriola L, Gareiss PC, Pantouris G, Tzouvelekis A, Kaminski N, Zhang X, Yu J, Jamali H, Ellman JA, Lolis E, Anderson KS, Bennett AM. Sci Signal 13 eaba3043 (2020)
  7. Letter Crystal structure of monkeypox H1 phosphatase, an antiviral drug target. Cui W, Huang H, Duan Y, Luo Z, Wang H, Zhang T, Nguyen HC, Shen W, Su D, Li X, Ji X, Yang H, Wang W. Protein Cell 14 469-472 (2023)
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