9tm5
Crystal structure of JAK2 JH1 in complex with AT9283
Structural highlights
DiseaseJAK2_HUMAN Note=Chromosomal aberrations involving JAK2 are found in both chronic and acute forms of eosinophilic, lymphoblastic and myeloid leukemia. Translocation t(8;9)(p22;p24) with PCM1 links the protein kinase domain of JAK2 to the major portion of PCM1. Translocation t(9;12)(p24;p13) with ETV6. Defects in JAK2 are a cause of susceptibility to Budd-Chiari syndrome (BDCHS) [MIM:600880. A syndrome caused by obstruction of hepatic venous outflow involving either the hepatic veins or the terminal segment of the inferior vena cava. Obstructions are generally caused by thrombosis and lead to hepatic congestion and ischemic necrosis. Clinical manifestations observed in the majority of patients include hepatomegaly, right upper quadrant pain and abdominal ascites. Budd-Chiari syndrome is associated with a combination of disease states including primary myeloproliferative syndromes and thrombophilia due to factor V Leiden, protein C deficiency and antithrombin III deficiency. Budd-Chiari syndrome is a rare but typical complication in patients with polycythemia vera. Defects in JAK2 are a cause of polycythemia vera (PV) [MIM:263300. A myeloproliferative disorder characterized by abnormal proliferation of all hematopoietic bone marrow elements, erythroid hyperplasia, an absolute increase in total blood volume, but also by myeloid leukocytosis, thrombocytosis and splenomegaly.[1] [2] [3] [4] Defects in JAK2 gene may be the cause of thrombocythemia type 3 (THCYT3) [MIM:614521. A myeloproliferative disorder characterized by elevated platelet levels due to sustained proliferation of megakaryocytes, and frequently lead to thrombotic and haemorrhagic complications.[5] [6] Defects in JAK2 are a cause of myelofibrosis (MYELOF) [MIM:254450. Myelofibrosis is a disorder characterized by replacement of the bone marrow by fibrous tissue, occurring in association with a myeloproliferative disorder. Clinical manifestations may include anemia, pallor, splenomegaly, hypermetabolic state, petechiae, ecchymosis, bleeding, lymphadenopathy, hepatomegaly, portal hypertension. Defects in JAK2 are a cause of acute myelogenous leukemia (AML) [MIM:601626. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development.[7] FunctionJAK2_HUMAN Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications. Mediates essential signaling events in both innate and adaptive immunity. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors such as growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR), thrombopoietin (THPO); or type II receptors including IFN-alpha, IFN-beta, IFN-gamma and multiple interleukins. Following ligand-binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins. Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, cell stimulation with erythropoietin (EPO) during erythropoiesis leads to JAK2 autophosphorylation, activation, and its association with erythropoietin receptor (EPOR) that becomes phosphorylated in its cytoplasmic domain. Then, STAT5 (STAT5A or STAT5B) is recruited, phosphorylated and activated by JAK2. Once activated, dimerized STAT5 translocates into the nucleus and promotes the transcription of several essential genes involved in the modulation of erythropoiesis. In addition, JAK2 mediates angiotensin-2-induced ARHGEF1 phosphorylation. Plays a role in cell cycle by phosphorylating CDKN1B. Cooperates with TEC through reciprocal phosphorylation to mediate cytokine-driven activation of FOS transcription. In the nucleus, plays a key role in chromatin by specifically mediating phosphorylation of 'Tyr-41' of histone H3 (H3Y41ph), a specific tag that promotes exclusion of CBX5 (HP1 alpha) from chromatin.[8] [9] [10] [11] Publication Abstract from PubMedTuberculosis remains one of the leading major global health challenges, driven by the emergence of multidrug-resistant and extensively drug-resistant bacterial strains. Resistant strains complicate treatment, which often requires prolonged use of toxic second- and third-line drugs. Protein phosphorylation plays critical roles in Mycobacterium tuberculosis, with serine/threonine kinases PknA, PknB, and PknG being essential for survival, virulence, and persistence. In this study, we screened an in-house kinase inhibitor library to identify compounds targeting these kinases. Four structurally diverse hits from the screening inhibiting all three kinases in vitro were selected for further analysis. Hits were evaluated for their ability to inhibit M. tuberculosis growth and characterized structurally using X-ray crystallography, molecular docking, and isothermal titration calorimetry. Our findings provide a structural framework for the development of multitargeting kinase inhibitors, offering a potential strategy to combat drug-resistant M. tuberculosis.IMPORTANCEDrug-resistant tuberculosis is a growing global health threat that is increasingly difficult to treat with existing antibiotics, necessitating the discovery of new therapeutic strategies. This study focuses on protein kinases, key regulatory enzymes that help Mycobacterium tuberculosis survive, cause disease, and persist in the host. By identifying small molecules that can simultaneously block multiple essential kinases, this work introduces a promising multitarget approach to combat tuberculosis. Using structural and biophysical methods, we reveal how these compounds interact with their targets, providing a clear blueprint for improving their effectiveness. These insights advance the rational design of next-generation antitubercular drugs and open new avenues for tackling multidrug- and extensively drug-resistant tuberculosis. Structural insights into multitargeting Mycobacterium tuberculosis Pkn kinases.,Pollaniemi A, Miao Y, Laitila L, Piippo H, Hammaren M, Parikka M, Haikarainen T Microbiol Spectr. 2026 Jul 14:e0004926. doi: 10.1128/spectrum.00049-26. PMID:42446239[12] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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