5dh3

From Proteopedia

Jump to: navigation, search

Crystal structure of MST2 in complex with XMU-MP-1

Structural highlights

5dh3 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.468Å
Ligands:5BS, CL, SO4, TPO
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

STK3_HUMAN Stress-activated, pro-apoptotic kinase which, following caspase-cleavage, enters the nucleus and induces chromatin condensation followed by internucleosomal DNA fragmentation. Key component of the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. STK3/MST2 and STK4/MST1 are required to repress proliferation of mature hepatocytes, to prevent activation of facultative adult liver stem cells (oval cells), and to inhibit tumor formation. Phosphorylates NKX2-1 (By similarity). Phosphorylates NEK2 and plays a role in centrosome disjunction by regulating the localization of NEK2 to centrosome, and its ability to phosphorylate CROCC and CEP250. In conjunction with SAV1, activates the transcriptional activity of ESR1 through the modulation of its phosphorylation. Positively regulates RAF1 activation via suppression of the inhibitory phosphorylation of RAF1 on 'Ser-259'. Phosphorylates MOBKL1A and RASSF2. Phosphorylates MOBKL1B on 'Thr-74'. Acts cooperatively with MOBKL1B to activate STK38.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10]

Publication Abstract from PubMed

Tissue repair and regenerative medicine address the important medical needs to replace damaged tissue with functional tissue. Most regenerative medicine strategies have focused on delivering biomaterials and cells, yet there is the untapped potential for drug-induced regeneration with good specificity and safety profiles. The Hippo pathway is a key regulator of organ size and regeneration by inhibiting cell proliferation and promoting apoptosis. Kinases MST1 and MST2 (MST1/2), the mammalian Hippo orthologs, are central components of this pathway and are, therefore, strong target candidates for pharmacologically induced tissue regeneration. We report the discovery of a reversible and selective MST1/2 inhibitor, 4-((5,10-dimethyl-6-oxo-6,10-dihydro-5H-pyrimido[5,4-b]thieno[3,2-e][1,4]diazepin -2-yl)amino)benzenesulfonamide (XMU-MP-1), using an enzyme-linked immunosorbent assay-based high-throughput biochemical assay. The cocrystal structure and the structure-activity relationship confirmed that XMU-MP-1 is on-target to MST1/2. XMU-MP-1 blocked MST1/2 kinase activities, thereby activating the downstream effector Yes-associated protein and promoting cell growth. XMU-MP-1 displayed excellent in vivo pharmacokinetics and was able to augment mouse intestinal repair, as well as liver repair and regeneration, in both acute and chronic liver injury mouse models at a dose of 1 to 3 mg/kg via intraperitoneal injection. XMU-MP-1 treatment exhibited substantially greater repopulation rate of human hepatocytes in the Fah-deficient mouse model than in the vehicle-treated control, indicating that XMU-MP-1 treatment might facilitate human liver regeneration. Thus, the pharmacological modulation of MST1/2 kinase activities provides a novel approach to potentiate tissue repair and regeneration, with XMU-MP-1 as the first lead for the development of targeted regenerative therapeutics.

Pharmacological targeting of kinases MST1 and MST2 augments tissue repair and regeneration.,Fan F, He Z, Kong LL, Chen Q, Yuan Q, Zhang S, Ye J, Liu H, Sun X, Geng J, Yuan L, Hong L, Xiao C, Zhang W, Sun X, Li Y, Wang P, Huang L, Wu X, Ji Z, Wu Q, Xia NS, Gray NS, Chen L, Yun CH, Deng X, Zhou D Sci Transl Med. 2016 Aug 17;8(352):352ra108. doi: 10.1126/scitranslmed.aaf2304. PMID:27535619[11]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Loading citation details..
Citations
reviews cite this structure
-1 more
other articles
No citations found

See Also

References

  1. ↑ Creasy CL, Chernoff J. Cloning and characterization of a member of the MST subfamily of Ste20-like kinases. Gene. 1995 Dec 29;167(1-2):303-6. PMID:8566796
  2. ↑ Taylor LK, Wang HC, Erikson RL. Newly identified stress-responsive protein kinases, Krs-1 and Krs-2. Proc Natl Acad Sci U S A. 1996 Sep 17;93(19):10099-104. PMID:8816758
  3. ↑ Chan EH, Nousiainen M, Chalamalasetty RB, Schafer A, Nigg EA, Sillje HH. The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1. Oncogene. 2005 Mar 17;24(12):2076-86. PMID:15688006 doi:1208445
  4. ↑ Callus BA, Verhagen AM, Vaux DL. Association of mammalian sterile twenty kinases, Mst1 and Mst2, with hSalvador via C-terminal coiled-coil domains, leads to its stabilization and phosphorylation. FEBS J. 2006 Sep;273(18):4264-76. Epub 2006 Aug 23. PMID:16930133 doi:EJB5427
  5. ↑ Praskova M, Xia F, Avruch J. MOBKL1A/MOBKL1B phosphorylation by MST1 and MST2 inhibits cell proliferation. Curr Biol. 2008 Mar 11;18(5):311-21. doi: 10.1016/j.cub.2008.02.006. PMID:18328708 doi:10.1016/j.cub.2008.02.006
  6. ↑ Hirabayashi S, Nakagawa K, Sumita K, Hidaka S, Kawai T, Ikeda M, Kawata A, Ohno K, Hata Y. Threonine 74 of MOB1 is a putative key phosphorylation site by MST2 to form the scaffold to activate nuclear Dbf2-related kinase 1. Oncogene. 2008 Jul 17;27(31):4281-92. doi: 10.1038/onc.2008.66. Epub 2008 Mar 24. PMID:18362890 doi:10.1038/onc.2008.66
  7. ↑ Cooper WN, Hesson LB, Matallanas D, Dallol A, von Kriegsheim A, Ward R, Kolch W, Latif F. RASSF2 associates with and stabilizes the proapoptotic kinase MST2. Oncogene. 2009 Aug 20;28(33):2988-98. doi: 10.1038/onc.2009.152. Epub 2009 Jun, 15. PMID:19525978 doi:10.1038/onc.2009.152
  8. ↑ Kilili GK, Kyriakis JM. Mammalian Ste20-like kinase (Mst2) indirectly supports Raf-1/ERK pathway activity via maintenance of protein phosphatase-2A catalytic subunit levels and consequent suppression of inhibitory Raf-1 phosphorylation. J Biol Chem. 2010 May 14;285(20):15076-87. doi: 10.1074/jbc.M109.078915. Epub, 2010 Mar 8. PMID:20212043 doi:10.1074/jbc.M109.078915
  9. ↑ Mardin BR, Lange C, Baxter JE, Hardy T, Scholz SR, Fry AM, Schiebel E. Components of the Hippo pathway cooperate with Nek2 kinase to regulate centrosome disjunction. Nat Cell Biol. 2010 Dec;12(12):1166-76. doi: 10.1038/ncb2120. Epub 2010 Nov 14. PMID:21076410 doi:10.1038/ncb2120
  10. ↑ Park Y, Park J, Lee Y, Lim W, Oh BC, Shin C, Kim W, Lee Y. Mammalian MST2 kinase and human Salvador activate and reduce estrogen receptor alpha in the absence of ligand. J Mol Med (Berl). 2011 Feb;89(2):181-91. doi: 10.1007/s00109-010-0698-y. Epub, 2010 Nov 23. PMID:21104395 doi:10.1007/s00109-010-0698-y
  11. ↑ Fan F, He Z, Kong LL, Chen Q, Yuan Q, Zhang S, Ye J, Liu H, Sun X, Geng J, Yuan L, Hong L, Xiao C, Zhang W, Sun X, Li Y, Wang P, Huang L, Wu X, Ji Z, Wu Q, Xia NS, Gray NS, Chen L, Yun CH, Deng X, Zhou D. Pharmacological targeting of kinases MST1 and MST2 augments tissue repair and regeneration. Sci Transl Med. 2016 Aug 17;8(352):352ra108. doi: 10.1126/scitranslmed.aaf2304. PMID:27535619 doi:http://dx.doi.org/10.1126/scitranslmed.aaf2304

Contents


PDB ID 5dh3

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://proteopedia.org/wiki/index.php/5dh3"
Personal tools