6dbm

From Proteopedia

(Difference between revisions)

Current revision

Tyk2 with compound 23

Structural highlights

6dbm is a 1 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 2.368Å
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

Cytokine signaling is an important characteristic of autoimmune diseases. Many pro-inflammatory cytokines signal through the Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) pathway. JAK1 is important for the gamma-common chain cytokines, interleukin (IL)-6, and type-I interferon (IFN) family, while TYK2 in addition to type-I IFN signaling also plays a role in IL-23 and IL-12 signaling. Intervention with monoclonal antibodies (mAbs) or JAK1 inhibitors has demonstrated efficacy in Phase III psoriasis, psoriatic arthritis, inflammatory bowel disease, and rheumatoid arthritis studies, leading to multiple drug approvals. We hypothesized that a dual JAK1/TYK2 inhibitor will provide additional efficacy, while managing risk by optimizing selectivity against JAK2 driven hematopoietic changes. Our program began with a conformationally constrained piperazinyl-pyrimidine Type 1 ATP site inhibitor, subsequent work led to the discovery of PF-06700841 (compound 23), which is in Phase II clinical development (NCT02969018, NCT02958865, NCT03395184, and NCT02974868).

Dual Inhibition of TYK2 and JAK1 for the Treatment of Autoimmune Diseases: Discovery of (( S)-2,2-Difluorocyclopropyl)((1 R,5 S)-3-(2-((1-methyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (PF-06700841).,Fensome A, Ambler CM, Arnold E, Banker ME, Brown MF, Chrencik J, Clark JD, Dowty ME, Efremov IV, Flick A, Gerstenberger BS, Gopalsamy A, Hayward MM, Hegen M, Hollingshead BD, Jussif J, Knafels JD, Limburg DC, Lin D, Lin TH, Pierce BS, Saiah E, Sharma R, Symanowicz PT, Telliez JB, Trujillo JI, Vajdos FF, Vincent F, Wan ZK, Xing L, Yang X, Yang X, Zhang L J Med Chem. 2018 Aug 16. doi: 10.1021/acs.jmedchem.8b00917. PMID:30113844^[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
↑ Fensome A, Ambler CM, Arnold E, Banker ME, Brown MF, Chrencik J, Clark JD, Dowty ME, Efremov IV, Flick A, Gerstenberger BS, Gopalsamy A, Hayward MM, Hegen M, Hollingshead BD, Jussif J, Knafels JD, Limburg DC, Lin D, Lin TH, Pierce BS, Saiah E, Sharma R, Symanowicz PT, Telliez JB, Trujillo JI, Vajdos FF, Vincent F, Wan ZK, Xing L, Yang X, Yang X, Zhang L. Dual Inhibition of TYK2 and JAK1 for the Treatment of Autoimmune Diseases: Discovery of (( S)-2,2-Difluorocyclopropyl)((1 R,5 S)-3-(2-((1-methyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (PF-06700841). J Med Chem. 2018 Aug 16. doi: 10.1021/acs.jmedchem.8b00917. PMID:30113844 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b00917

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/6dbm"

Categories: Homo sapiens | Large Structures | Vajdos FF

@@ Line 1: / Line 1: @@
 ==Tyk2 with compound 23==
-<StructureSection load='6dbm' size='340' side='right' caption='[[6dbm]], [[Resolution|resolution]] 2.37&Aring;' scene=''>
+<StructureSection load='6dbm' size='340' side='right'caption='[[6dbm]], [[Resolution|resolution]] 2.37&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6dbm]] is a 1 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=6DBM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DBM FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6dbm]] is a 1 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=6DBM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6DBM FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=G4J:[(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octan-8-yl]methanone'>G4J</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]] 2.368&#8491;</td></tr>
-<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=G4J:[(1~{S})-2,2-bis(fluoranyl)cyclopropyl]-[(1~{R},5~{S})-3-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]methanone'>G4J</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6dbm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dbm OCA], [https://pdbe.org/6dbm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6dbm RCSB], [https://www.ebi.ac.uk/pdbsum/6dbm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6dbm ProSAT]</span></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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6dbm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dbm OCA], [http://pdbe.org/6dbm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6dbm RCSB], [http://www.ebi.ac.uk/pdbsum/6dbm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6dbm 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 25: / 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: Vajdos, F F]]
+[[Category: Vajdos FF]]
-[[Category: Kinase]]
-[[Category: Transferase]]

6dbm

From Proteopedia

Current revision

Tyk2 with compound 23

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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