Structural and Functional Characterization of the JH2 Pseudokinase Domain of JAK Family Tyrosine Kinase 2 (TYK2)

Min, Xiaoshan; Ungureanu, Daniela; Maxwell, Sarah Sollid; Hammarén, Henrik M.; Thibault, Steve; Hillert, Ellin-Kristina; Ayres, Merrill; Greenfield, B. W.; Eksterowicz, John; Gabel, Chris; Walker, Nigel; Silvennoinen, Olli; Wang, Zhong Lin

doi:10.1074/jbc.m115.672048

Cited by 79 publications

(90 citation statements)

References 45 publications

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“…X-ray crystallography gives atomic-level information on the structure of a nt-binding pocket and can be used to predict, or in the case of nt-bound structures, unequivocally verify nt binding. KSR2 [ 4 ], HER3 [ 5 , 36 ], TYK2 JH2 [ 37 ], JAK2 JH2 [ 38 ], STE20-related adaptor alpha (STRADα) [ 39 ], ILK [ 40 ] and CASK [ 7 ], as well as a few other pseudokinases and PKLs from human and other species, have been crystallized in complex with nts providing solid proof and mechanistic information of nt binding (see Table 1 ). While X-ray crystallography is limited to determination of rigid protein structures, NMR is applicable for small proteins ( M r ≤30–40 kDa [ 41 ]) in a soluble state to reveal dynamic structures [ 42 ], and e.g.…”

Section: Methodology Of Measuring Nt Bindingmentioning

confidence: 99%

“…ITC is the only method for direct measurement of thermodynamic parameters including enthalpy, K d and stoichiometry for ligand–protein interaction, as it directly measures the absorbed or emitted heat during a (bio)molecular interaction [ 34 ]. SPR, on the other hand, provides direct information about binding kinetics and affinity through an optical assay [ 37 , 44 ].…”

Section: Methodology Of Measuring Nt Bindingmentioning

confidence: 99%

“…The most prominent of these mutations is the V617F mutation in JAK2 JH2 underlying multiple myeloproliferative neoplasms [ 64 ]. While JAK2 JH2 has been shown to possess low autoregulatory kinase activity [ 6 ], JAK1 and TYK2 JH2s are probably catalytically inactive pseudokinases as no autophosphorylation or kinase activity towards exogenous substrates has been detected [ 37 , 65 ].…”

Section: Modes Of Nt Binding In Pseudokinasesmentioning

confidence: 99%

“…Three of the four JAK JH2 domain structures have been solved over the last few years. The JH2s in all three (JAK1, JAK2, TYK2) are very similar and show a kinase domain structure with an accessible nt-binding site, a partially degraded Gly-rich loop (Gly 50 and Gly 52 are present, however) and an abnormally short activation loop [ 37 , 38 , 65 ]. The structures resemble the HER3 PKD in their nt-binding site architecture, as the canonical Lys 72 –Glu 91 bond is replaced with a Lys 72 –Asp 184 bond and an asparagine substitutes for Asp 166 in the catalytic loop ( Figure 1 ).…”

Section: Modes Of Nt Binding In Pseudokinasesmentioning

confidence: 99%

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Nucleotide-binding mechanisms in pseudokinases

2016

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Pseudokinases are classified by the lack of one or several of the highly conserved motifs involved in nucleotide (nt) binding or catalytic activity of protein kinases (PKs). Pseudokinases represent ∼10% of the human kinome and they are found in all evolutionary classes of kinases. It has become evident that pseudokinases, which were initially considered somewhat peculiar dead kinases, are important components in several signalling cascades. Furthermore, several pseudokinases have been linked to human diseases, particularly cancer, which is raising interest for therapeutic approaches towards these proteins. The ATP-binding pocket is a well-established drug target and elucidation of the mechanism and properties of nt binding in pseudokinases is of significant interest and importance. Recent studies have demonstrated that members of the pseudokinase family are very diverse in structure as well as in their ability and mechanism to bind nts or perform phosphoryl transfer reactions. This diversity also precludes prediction of pseudokinase function, or the importance of nt binding for said function, based on primary sequence alone. Currently available data indicate that ∼40% of pseudokinases are able to bind nts, whereas only few are able to catalyse occasional phosphoryl transfer. Pseudokinases employ diverse mechanisms to bind nts, which usually occurs at low, but physiological, affinity. ATP binding serves often a structural role but in most cases the functional roles are not precisely known. In the present review, we discuss the various mechanisms that pseudokinases employ for nt binding and how this often low-affinity binding can be accurately analysed.

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Section: Methodology Of Measuring Nt Bindingmentioning

confidence: 99%

Section: Methodology Of Measuring Nt Bindingmentioning

confidence: 99%

Section: Modes Of Nt Binding In Pseudokinasesmentioning

confidence: 99%

Section: Modes Of Nt Binding In Pseudokinasesmentioning

confidence: 99%

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Nucleotide-binding mechanisms in pseudokinases

2016

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“…The mechanism is best understood for TYK2 at the type I IFN receptor (IFNAR) in human cells [40,41] and is similar for other cytokine/receptor combinations [42,43]. The conformational changes of ligand-bound cytokine receptors release the autoinhibitory intramolecular fold of the kinase domain [44][45][46]. In the case of TYK2, this leads to enzymatic activation by phosphorylation of two conserved tyrosine residues in the activation loop (Y1054/Y1055 in men and Y1047/Y1048 in mice) by transactivation of the adjacent JAK1/2 or by autophosphorylation.…”

Section: Identification and Structure-function Relations Of Tyk2mentioning

confidence: 99%

TYK2 in Tumor Immunosurveillance

Karjalainen¹,

Shoebridge²,

Krunic³

et al. 2020

Cancers

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We review the history of the tyrosine kinase 2 (TYK2) as the founding member of the Janus kinase (JAK) family and outline its structure-function relation. Gene-targeted mice and hereditary defects of TYK2 in men have established the biological and pathological functions of TYK2 in innate and adaptive immune responses to infection and cancer and in (auto-)inflammation. We describe the architecture of the main cytokine receptor families associated with TYK2, which activate signal transducers and activators of transcription (STATs). We summarize the cytokine receptor activities with well characterized dependency on TYK2, the types of cells that respond to cytokines and TYK2 signaling-induced cytokine production. TYK2 may drive beneficial or detrimental activities, which we explain based on the concepts of tumor immunoediting and the cancer-immunity cycle in the tumor microenvironment. Finally, we summarize current knowledge of TYK2 functions in mouse models of tumor surveillance. The biology and biochemistry of JAKs, TYK2-dependent cytokines and cytokine signaling in tumor surveillance are well covered in recent reviews and the oncogenic properties of TYK2 are reviewed in the recent Special Issue ‘Targeting STAT3 and STAT5 in Cancer’ of Cancers.

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JAK Family Inhibitors for Autoimmune Diseases

Borzilleri

Hart

Moslin

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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The JAK family of non‐receptor tyrosine kinases mediates the signaling of proinflammatory cytokines that contribute to the pathogenesis of numerous autoimmune diseases. While cytokine‐directed therapies are available to treat immune‐driven diseases, oral small‐molecule inhibitors of the JAK family (Jakinibs) have been approved as viable alternatives for the treatment of RA, PsA, and IBD. These first‐generation pan‐JAK inhibitors target the highly conserved catalytically active kinase domains in a reversible, ATP‐competitive manner, albeit in a nonselective fashion. Novel approaches to target alternative binding modes through, for example irreversible or allosteric kinase inhibition, have led to the identification of the next generation of agents, which demonstrate improved JAK family selectivity. This improved selectivity offers the potential for greater and perhaps broader efficacy by allowing for higher dosing, while avoiding undesired side effects. This article provides an overview of the JAK‐STAT signaling pathway and outlines the challenges associated with the discovery of selective JAK inhibitors while highlighting a unique allosteric TYK2 inhibitor. For each of the agents discussed, a synopsis of the medicinal chemistry efforts leading to a particular molecule is provided along with a brief summary of available preclinical and clinical efficacy and safety data.

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Structural and Functional Characterization of the JH2 Pseudokinase Domain of JAK Family Tyrosine Kinase 2 (TYK2)

Cited by 79 publications

References 45 publications

Nucleotide-binding mechanisms in pseudokinases

Nucleotide-binding mechanisms in pseudokinases

TYK2 in Tumor Immunosurveillance

JAK Family Inhibitors for Autoimmune Diseases

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