6vns: Difference between revisions

Latest revision as of 08:15, 11 October 2023

Crystal structure of TYK2 kinase with compound 13

Structural highlights

6vns 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 2.09Å
Ligands:	PTR, R5D
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

Herein, we disclose a new series of TYK2/ JAK1 inhibitors based upon a 3.1.0 azabicyclic substituted pyrimidine scaffold. We illustrate the use of structure-based drug design for the initial design and subsequent optimization of this series of compounds. One advanced example 19 met program objectives for potency, selectivity and ADME, and demonstrated oral activity in the adjuvant-induced arthritis rat model.

Design and optimization of a series of 4-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-2-amines: Dual inhibitors of TYK2 and JAK1.,Fensome A, Ambler CM, Arnold E, Banker ME, Clark JD, Dowty ME, Efremov IV, Flick A, Gerstenberger BS, Gifford RS, Gopalsamy A, Hegen M, Jussif J, Limburg DC, Lin TH, Pierce BS, Sharma R, Trujillo JI, Vajdos FF, Vincent F, Wan ZK, Xing L, Yang X, Yang X Bioorg Med Chem. 2020 May 15;28(10):115481. doi: 10.1016/j.bmc.2020.115481. Epub , 2020 Mar 31. PMID:32253095^[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, Clark JD, Dowty ME, Efremov IV, Flick A, Gerstenberger BS, Gifford RS, Gopalsamy A, Hegen M, Jussif J, Limburg DC, Lin TH, Pierce BS, Sharma R, Trujillo JI, Vajdos FF, Vincent F, Wan ZK, Xing L, Yang X, Yang X. Design and optimization of a series of 4-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-2-amines: Dual inhibitors of TYK2 and JAK1. Bioorg Med Chem. 2020 May 15;28(10):115481. doi: 10.1016/j.bmc.2020.115481. Epub , 2020 Mar 31. PMID:32253095 doi:https://dx.doi.org/10.1016/j.bmc.2020.115481

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] 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

[2] Fensome A, Ambler CM, Arnold E, Banker ME, Clark JD, Dowty ME, Efremov IV, Flick A, Gerstenberger BS, Gifford RS, Gopalsamy A, Hegen M, Jussif J, Limburg DC, Lin TH, Pierce BS, Sharma R, Trujillo JI, Vajdos FF, Vincent F, Wan ZK, Xing L, Yang X, Yang X. Design and optimization of a series of 4-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-2-amines: Dual inhibitors of TYK2 and JAK1. Bioorg Med Chem. 2020 May 15;28(10):115481. doi: 10.1016/j.bmc.2020.115481. Epub , 2020 Mar 31. PMID:32253095 doi:https://dx.doi.org/10.1016/j.bmc.2020.115481

[1]

[2]

@@ Line 3: / Line 3: @@
 <StructureSection load='6vns' size='340' side='right'caption='[[6vns]], [[Resolution|resolution]] 2.09&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6vns]] 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=6VNS OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6VNS FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6vns]] 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=6VNS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6VNS FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=R5D:(1R,2R)-2-cyano-N-[(1S,5R)-3-(5-fluoro-2-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl]cyclopropane-1-carboxamide'>R5D</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]] 2.09&#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=PTR:O-PHOSPHOTYROSINE'>PTR</scene>, <scene name='pdbligand=R5D:(1R,2R)-2-cyano-N-[(1S,5R)-3-(5-fluoro-2-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl]cyclopropane-1-carboxamide'>R5D</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=6vns FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vns OCA], [https://pdbe.org/6vns PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6vns RCSB], [https://www.ebi.ac.uk/pdbsum/6vns PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6vns 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://proteopedia.org/fgij/fg.htm?mol=6vns FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vns OCA], [http://pdbe.org/6vns PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6vns RCSB], [http://www.ebi.ac.uk/pdbsum/6vns PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6vns 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 27: / Line 25: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Non-specific protein-tyrosine kinase]]
+[[Category: Vajdos FF]]
-[[Category: Vajdos, F F]]
-[[Category: Kinase]]
-[[Category: Transferase]]
-[[Category: Transferase-inhibitor complex]]

6vns: Difference between revisions

Latest revision as of 08:15, 11 October 2023

Crystal structure of TYK2 kinase with compound 13

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Navigation menu

Page actions

Page actions

Personal tools

Navigation

Search

Tools