5tkd

From Proteopedia

(Difference between revisions)

Current revision

CRYSTAL STRUCTURE OF TYROSINE KINASE 2 JH2 (PSEUDO KINASE DOMAIN) COMPLEXED WITH 6-[(3,5-DIMETHYLPHE NYL)AMINO]-8- (METHYLAMINO)IMIDAZO[1,2-B]PYRIDAZINE-3-CARBO XAMIDE

Structural highlights

5tkd 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 1.92Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

TYK2_HUMAN Mendelian susceptibility to mycobacterial diseases;Autosomal recessive hyper IgE syndrome. Defects in TYK2 are the cause of protein-tyrosine kinase 2 deficiency (TYK2 deficiency) [MIM:611521; also known as autosomal recessive hyper-IgE syndrome (HIES) with atypical mycobacteriosis. TYK2 deficiency consists of a primary immunodeficiency characterized by recurrent skin abscesses, pneumonia, and highly elevated serum IgE.

Function

TYK2_HUMAN Probably involved in intracellular signal transduction by being involved in the initiation of type I IFN signaling. Phosphorylates the interferon-alpha/beta receptor alpha chain.^[1]

Publication Abstract from PubMed

As a member of the Janus (JAK) family of non-receptor tyrosine kinases, TYK2 mediates the signaling of pro-inflammatory cytokines including IL-12, IL-23 and type 1 interferon (IFN), and therefore represents an attractive potential target for treating the various immuno-inflammatory diseases in which these cytokines have been shown to play a role. Following up on our previous report that ligands to the pseudokinase domain (JH2) of TYK2 suppress cytokine-mediated receptor activation of the catalytic (JH1) domain, the imidazo[1,2-b]pyridazine (IZP) 7 was identified as a promising hit compound. Through iterative modification of each of the substituents of the IZP scaffold, the cellular potency was improved while maintaining selectivity over the JH1 domain. These studies led to the discovery of the JH2-selective TYK2 inhibitor 29, which provided encouraging systemic exposures after oral dosing in mice. Phosphodiesterase 4 (PDE4) was identified as an off-target and potential liability of the IZP ligands, and selectivity for TYK2 JH2 over this enzyme was obtained by elaborating along selectivity vectors determined from analyses of X-ray co-crystal structures of representative ligands of the IZP class bound to both proteins.

Identification of imidazo[1,2-b]pyridazine TYK2 pseudokinase ligands as potent and selective allosteric inhibitors of TYK2 signalling.,Moslin R, Gardner D, Santella J, Zhang Y, Duncia JV, Liu C, Lin J, Tokarski JS, Strnad J, Pedicord D, Chen J, Blat Y, Zupa-Fernandez A, Cheng L, Sun H, Chaudhry C, Huang C, D'Arienzo C, Sack JS, Muckelbauer JK, Chang C, Tredup J, Xie D, Aranibar N, Burke JR, Carter PH, Weinstein DS Medchemcomm. 2016 Dec 15;8(4):700-712. doi: 10.1039/c6md00560h. eCollection 2017 , Apr 1. PMID:30108788^[2]

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

References

↑ Colamonici O, Yan H, Domanski P, Handa R, Smalley D, Mullersman J, Witte M, Krishnan K, Krolewski J. Direct binding to and tyrosine phosphorylation of the alpha subunit of the type I interferon receptor by p135tyk2 tyrosine kinase. Mol Cell Biol. 1994 Dec;14(12):8133-42. PMID:7526154
↑ Moslin R, Gardner D, Santella J, Zhang Y, Duncia JV, Liu C, Lin J, Tokarski JS, Strnad J, Pedicord D, Chen J, Blat Y, Zupa-Fernandez A, Cheng L, Sun H, Chaudhry C, Huang C, D'Arienzo C, Sack JS, Muckelbauer JK, Chang C, Tredup J, Xie D, Aranibar N, Burke JR, Carter PH, Weinstein DS. Identification of imidazo[1,2-b]pyridazine TYK2 pseudokinase ligands as potent and selective allosteric inhibitors of TYK2 signalling. Medchemcomm. 2016 Dec 15;8(4):700-712. doi: 10.1039/c6md00560h. eCollection 2017 , Apr 1. PMID:30108788 doi:http://dx.doi.org/10.1039/c6md00560h

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5tkd"

Categories: Homo sapiens | Large Structures | Muckelbauer JK

@@ Line 1: / Line 1: @@
 ==CRYSTAL STRUCTURE OF TYROSINE KINASE 2 JH2 (PSEUDO KINASE DOMAIN) COMPLEXED WITH 6-[(3,5-DIMETHYLPHE NYL)AMINO]-8- (METHYLAMINO)IMIDAZO[1,2-B]PYRIDAZINE-3-CARBO XAMIDE==
-<StructureSection load='5tkd' size='340' side='right' caption='[[5tkd]], [[Resolution|resolution]] 1.92&Aring;' scene=''>
+<StructureSection load='5tkd' size='340' side='right'caption='[[5tkd]], [[Resolution|resolution]] 1.92&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5tkd]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TKD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TKD FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5tkd]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TKD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TKD FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7GL:6-[(3,5-DIMETHYLPHENYL)AMINO]-8-(METHYLAMINO)IMIDAZO[1,2-B]PYRIDAZINE-3-CARBOXAMIDE'>7GL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.92&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TYK2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7GL:6-[(3,5-DIMETHYLPHENYL)AMINO]-8-(METHYLAMINO)IMIDAZO[1,2-B]PYRIDAZINE-3-CARBOXAMIDE'>7GL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-<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'>[https://proteopedia.org/fgij/fg.htm?mol=5tkd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tkd OCA], [https://pdbe.org/5tkd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tkd RCSB], [https://www.ebi.ac.uk/pdbsum/5tkd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tkd ProSAT]</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=5tkd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tkd OCA], [http://pdbe.org/5tkd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tkd RCSB], [http://www.ebi.ac.uk/pdbsum/5tkd PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tkd ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://www.uniprot.org/uniprot/TYK2_HUMAN TYK2_HUMAN]] Mendelian susceptibility to mycobacterial diseases;Autosomal recessive hyper IgE syndrome. Defects in TYK2 are the cause of protein-tyrosine kinase 2 deficiency (TYK2 deficiency) [MIM:[http://omim.org/entry/611521 611521]]; also known as autosomal recessive hyper-IgE syndrome (HIES) with atypical mycobacteriosis. TYK2 deficiency consists of a primary immunodeficiency characterized by recurrent skin abscesses, pneumonia, and highly elevated serum IgE.
+[https://www.uniprot.org/uniprot/TYK2_HUMAN TYK2_HUMAN] Mendelian susceptibility to mycobacterial diseases;Autosomal recessive hyper IgE syndrome. Defects in TYK2 are the cause of protein-tyrosine kinase 2 deficiency (TYK2 deficiency) [MIM:[https://omim.org/entry/611521 611521]; also known as autosomal recessive hyper-IgE syndrome (HIES) with atypical mycobacteriosis. TYK2 deficiency consists of a primary immunodeficiency characterized by recurrent skin abscesses, pneumonia, and highly elevated serum IgE.
 == Function ==
-[[http://www.uniprot.org/uniprot/TYK2_HUMAN TYK2_HUMAN]] Probably involved in intracellular signal transduction by being involved in the initiation of type I IFN signaling. Phosphorylates the interferon-alpha/beta receptor alpha chain.<ref>PMID:7526154</ref>
+[https://www.uniprot.org/uniprot/TYK2_HUMAN TYK2_HUMAN] Probably involved in intracellular signal transduction by being involved in the initiation of type I IFN signaling. Phosphorylates the interferon-alpha/beta receptor alpha chain.<ref>PMID:7526154</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 24: / Line 23: @@
 ==See Also==
-*[[Tyrosine kinase|Tyrosine kinase]]
+*[[Tyrosine kinase 3D structures|Tyrosine kinase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
-[[Category: Non-specific protein-tyrosine kinase]]
+[[Category: Large Structures]]
-[[Category: Muckelbauer, J K]]
+[[Category: Muckelbauer JK]]
-[[Category: Kinase]]
-[[Category: Pseudokinase]]
-[[Category: Transferase]]
-[[Category: Tyk2]]

5tkd

From Proteopedia

Current revision

CRYSTAL STRUCTURE OF TYROSINE KINASE 2 JH2 (PSEUDO KINASE DOMAIN) COMPLEXED WITH 6-[(3,5-DIMETHYLPHE NYL)AMINO]-8- (METHYLAMINO)IMIDAZO[1,2-B]PYRIDAZINE-3-CARBO XAMIDE

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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