5lwn: Difference between revisions

From Proteopedia
Jump to navigation Jump to search
← Older editNewer edit →
m Protected "5lwn" [edit=sysop:move=sysop]
No edit summary
Line 1: Line 1:
'''Unreleased structure'''


The entry 5lwn is ON HOLD
==Crystal structure of JAK3 in complex with Compound 5 (FM409)==
 
<StructureSection load='5lwn' size='340' side='right' caption='[[5lwn]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
Authors: Chaikuad, A., Forster, M., Mukhopadhyay, S., Kupinska, K., Ellis, K., Mahajan, P., Edwards, A.M., Arrowsmith, C.H., Bountra, C., Laufer, S.A., Knapp, S., Structural Genomics Consortium (SGC)
== Structural highlights ==
 
<table><tr><td colspan='2'>[[5lwn]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LWN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5LWN FirstGlance]. <br>
Description: Crystal structure of JAK3 in complex with Compound 5 (FM409)
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=79R:(~{Z})-2-CYANO-~{N},~{N}-DIMETHYL-3-[5-[3-[(1~{S},2~{R})-2-METHYLCYCLOHEXYL]-3,5,8,10-TETRAZATRICYCLO[7.3.0.0^{2,6}]DODECA-1,4,6,8,11-PENTAEN-4-YL]FURAN-2-YL]PROP-2-ENAMIDE'>79R</scene>, <scene name='pdbligand=79S:(2~{S})-2-CYANO-~{N},~{N}-DIMETHYL-3-[5-[3-[(1~{S},2~{R})-2-METHYLCYCLOHEXYL]-3,5,8,10-TETRAZATRICYCLO[7.3.0.0^{2,6}]DODECA-1,4,6,8,11-PENTAEN-4-YL]FURAN-2-YL]PROPANAMIDE'>79S</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PHU:1-PHENYLUREA'>PHU</scene></td></tr>
[[Category: Unreleased Structures]]
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5lwn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lwn OCA], [http://pdbe.org/5lwn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5lwn RCSB], [http://www.ebi.ac.uk/pdbsum/5lwn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5lwn ProSAT]</span></td></tr>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/JAK3_HUMAN JAK3_HUMAN]] Defects in JAK3 are a cause of severe combined immunodeficiency autosomal recessive T-cell-negative/B-cell-positive/NK-cell-negative (T(-)B(+)NK(-) SCID) [MIM:[http://omim.org/entry/600802 600802]]. A form of severe combined immunodeficiency (SCID), a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients present in infancy recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development.<ref>PMID:15121872</ref> <ref>PMID:18250158</ref> <ref>PMID:15831699</ref> [:]<ref>PMID:7659163</ref> <ref>PMID:9354668</ref> <ref>PMID:9753072</ref> <ref>PMID:10982185</ref> <ref>PMID:14615376</ref> 
== Function ==
[[http://www.uniprot.org/uniprot/JAK3_HUMAN JAK3_HUMAN]] Non-receptor tyrosine kinase involved in various processes such as cell growth, development, or differentiation. Mediates essential signaling events in both innate and adaptive immunity and plays a crucial role in hematopoiesis during T-cells development. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors sharing the common subunit gamma such as IL2R, IL4R, IL7R, IL9R, IL15R and IL21R. 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, upon IL2R activation by IL2, JAK1 and JAK3 molecules bind to IL2R beta (IL2RB) and gamma chain (IL2RG) subunits inducing the tyrosine phosphorylation of both receptor subunits on their cytoplasmic domain. Then, STAT5A AND STAT5B are recruited, phosphorylated and activated by JAK1 and JAK3. Once activated, dimerized STAT5 translocates to the nucleus and promotes the transcription of specific target genes in a cytokine-specific fashion.<ref>PMID:8022485</ref> <ref>PMID:7662955</ref> <ref>PMID:20440074</ref> 
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Non-specific protein-tyrosine kinase]]
[[Category: Arrowsmith, C H]]
[[Category: Bountra, C]]
[[Category: Burgess-Brown, N]]
[[Category: Chaikuad, A]]
[[Category: Chaikuad, A]]
[[Category: Edwards, A M]]
[[Category: Ellis, K]]
[[Category: Forster, M]]
[[Category: Forster, M]]
[[Category: Laufer, S.A]]
[[Category: Knapp, S]]
[[Category: Knapp, S]]
[[Category: Mukhopadhyay, S]]
[[Category: Bountra, C]]
[[Category: Kupinska, K]]
[[Category: Kupinska, K]]
[[Category: Arrowsmith, C.H]]
[[Category: Laufer, S A]]
[[Category: Mahajan, P]]
[[Category: Mahajan, P]]
[[Category: Edwards, A.M]]
[[Category: Mukhopadhyay, S]]
[[Category: Ellis, K]]
[[Category: Structural genomic]]
[[Category: Structural Genomics Consortium (Sgc)]]
[[Category: Arginine pocket]]
[[Category: Covalent inhibitor]]
[[Category: Induced pocket]]
[[Category: Jak3]]
[[Category: Reversible covalent inhibitor]]
[[Category: Sgc]]
[[Category: Transferase]]

Revision as of 21:48, 26 October 2016

Crystal structure of JAK3 in complex with Compound 5 (FM409)Crystal structure of JAK3 in complex with Compound 5 (FM409)

Structural highlights

5lwn is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:, , ,
Activity:Non-specific protein-tyrosine kinase, with EC number 2.7.10.2
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[JAK3_HUMAN] Defects in JAK3 are a cause of severe combined immunodeficiency autosomal recessive T-cell-negative/B-cell-positive/NK-cell-negative (T(-)B(+)NK(-) SCID) [MIM:600802]. A form of severe combined immunodeficiency (SCID), a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients present in infancy recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development.[1] [2] [3] [:][4] [5] [6] [7] [8]

Function

[JAK3_HUMAN] Non-receptor tyrosine kinase involved in various processes such as cell growth, development, or differentiation. Mediates essential signaling events in both innate and adaptive immunity and plays a crucial role in hematopoiesis during T-cells development. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors sharing the common subunit gamma such as IL2R, IL4R, IL7R, IL9R, IL15R and IL21R. 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, upon IL2R activation by IL2, JAK1 and JAK3 molecules bind to IL2R beta (IL2RB) and gamma chain (IL2RG) subunits inducing the tyrosine phosphorylation of both receptor subunits on their cytoplasmic domain. Then, STAT5A AND STAT5B are recruited, phosphorylated and activated by JAK1 and JAK3. Once activated, dimerized STAT5 translocates to the nucleus and promotes the transcription of specific target genes in a cytokine-specific fashion.[9] [10] [11]

References

  1. ↑ Kurzer JH, Argetsinger LS, Zhou YJ, Kouadio JL, O'Shea JJ, Carter-Su C. Tyrosine 813 is a site of JAK2 autophosphorylation critical for activation of JAK2 by SH2-B beta. Mol Cell Biol. 2004 May;24(10):4557-70. PMID:15121872
  2. ↑ Cheng H, Ross JA, Frost JA, Kirken RA. Phosphorylation of human Jak3 at tyrosines 904 and 939 positively regulates its activity. Mol Cell Biol. 2008 Apr;28(7):2271-82. doi: 10.1128/MCB.01789-07. Epub 2008 Feb, 4. PMID:18250158 doi:10.1128/MCB.01789-07
  3. ↑ Boggon TJ, Li Y, Manley PW, Eck MJ. Crystal structure of the Jak3 kinase domain in complex with a staurosporine analog. Blood. 2005 Aug 1;106(3):996-1002. Epub 2005 Apr 14. PMID:15831699 doi:http://dx.doi.org/10.1182/blood-2005-02-0707
  4. ↑ Macchi P, Villa A, Giliani S, Sacco MG, Frattini A, Porta F, Ugazio AG, Johnston JA, Candotti F, O'Shea JJ, et al.. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature. 1995 Sep 7;377(6544):65-8. PMID:7659163 doi:http://dx.doi.org/10.1038/377065a0
  5. ↑ Candotti F, Oakes SA, Johnston JA, Giliani S, Schumacher RF, Mella P, Fiorini M, Ugazio AG, Badolato R, Notarangelo LD, Bozzi F, Macchi P, Strina D, Vezzoni P, Blaese RM, O'Shea JJ, Villa A. Structural and functional basis for JAK3-deficient severe combined immunodeficiency. Blood. 1997 Nov 15;90(10):3996-4003. PMID:9354668
  6. ↑ Bozzi F, Lefranc G, Villa A, Badolato R, Schumacher RF, Khalil G, Loiselet J, Bresciani S, O'Shea JJ, Vezzoni P, Notarangelo LD, Candotti F. Molecular and biochemical characterization of JAK3 deficiency in a patient with severe combined immunodeficiency over 20 years after bone marrow transplantation: implications for treatment. Br J Haematol. 1998 Sep;102(5):1363-6. PMID:9753072
  7. ↑ Schumacher RF, Mella P, Badolato R, Fiorini M, Savoldi G, Giliani S, Villa A, Candotti F, Tampalini A, O'Shea JJ, Notarangelo LD. Complete genomic organization of the human JAK3 gene and mutation analysis in severe combined immunodeficiency by single-strand conformation polymorphism. Hum Genet. 2000 Jan;106(1):73-9. PMID:10982185
  8. ↑ Roberts JL, Lengi A, Brown SM, Chen M, Zhou YJ, O'Shea JJ, Buckley RH. Janus kinase 3 (JAK3) deficiency: clinical, immunologic, and molecular analyses of 10 patients and outcomes of stem cell transplantation. Blood. 2004 Mar 15;103(6):2009-18. Epub 2003 Nov 13. PMID:14615376 doi:10.1182/blood-2003-06-2104
  9. ↑ Johnston JA, Kawamura M, Kirken RA, Chen YQ, Blake TB, Shibuya K, Ortaldo JR, McVicar DW, O'Shea JJ. Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2. Nature. 1994 Jul 14;370(6485):151-3. PMID:8022485 doi:http://dx.doi.org/10.1038/370151a0
  10. ↑ Sharfe N, Dadi HK, Roifman CM. JAK3 protein tyrosine kinase mediates interleukin-7-induced activation of phosphatidylinositol-3' kinase. Blood. 1995 Sep 15;86(6):2077-85. PMID:7662955
  11. ↑ Malamut G, El Machhour R, Montcuquet N, Martin-Lanneree S, Dusanter-Fourt I, Verkarre V, Mention JJ, Rahmi G, Kiyono H, Butz EA, Brousse N, Cellier C, Cerf-Bensussan N, Meresse B. IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis. J Clin Invest. 2010 Jun;120(6):2131-43. doi: 10.1172/JCI41344. Epub 2010 May 3. PMID:20440074 doi:10.1172/JCI41344

5lwn, resolution 1.60Å

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA
Retrieved from "https://proteopedia.openfox.io/wiki/index.php?title=5lwn&oldid=2685121"