6ova: Difference between revisions

Revision as of 04:18, 13 February 2020

Crystal Structure of TYK2 with novel pyrrolidinone inhibitor

Structural highlights

6ova is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	N9G
Activity:	Non-specific protein-tyrosine kinase, with EC number 2.7.10.2
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 report an efficient method for the synthesis of a highly functionalized 2-pyrrolidinone, tert-butyl 3-cyano-3-cyclopropyl-2-oxopyrrolidine-4-carboxylate, from readily available starting materials. Utility of this compound was demonstrated in the synthesis of a novel series of macrocyclic Tyk2 inhibitors, leading to the identification of a potent and selective macrocyclic Tyk2 inhibitor (26).

Efficient synthesis of tert-butyl 3-cyano-3-cyclopropyl-2-oxopyrrolidine-4-carboxylates: Highly functionalized 2-pyrrolidinone enabling access to novel macrocyclic Tyk2 inhibitors.,Sasaki Y, Tokuhara H, Ohba Y, Okabe A, Nakayama M, Nakagawa H, Skene R, Hoffman I, Zou H, Yoshida M Bioorg Med Chem Lett. 2020 Mar 1;30(5):126963. doi: 10.1016/j.bmcl.2020.126963., Epub 2020 Jan 13. PMID:31980341^[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
↑ Sasaki Y, Tokuhara H, Ohba Y, Okabe A, Nakayama M, Nakagawa H, Skene R, Hoffman I, Zou H, Yoshida M. Efficient synthesis of tert-butyl 3-cyano-3-cyclopropyl-2-oxopyrrolidine-4-carboxylates: Highly functionalized 2-pyrrolidinone enabling access to novel macrocyclic Tyk2 inhibitors. Bioorg Med Chem Lett. 2020 Mar 1;30(5):126963. doi: 10.1016/j.bmcl.2020.126963., Epub 2020 Jan 13. PMID:31980341 doi:https://dx.doi.org/10.1016/j.bmcl.2020.126963

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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] Sasaki Y, Tokuhara H, Ohba Y, Okabe A, Nakayama M, Nakagawa H, Skene R, Hoffman I, Zou H, Yoshida M. Efficient synthesis of tert-butyl 3-cyano-3-cyclopropyl-2-oxopyrrolidine-4-carboxylates: Highly functionalized 2-pyrrolidinone enabling access to novel macrocyclic Tyk2 inhibitors. Bioorg Med Chem Lett. 2020 Mar 1;30(5):126963. doi: 10.1016/j.bmcl.2020.126963., Epub 2020 Jan 13. PMID:31980341 doi:https://dx.doi.org/10.1016/j.bmcl.2020.126963

[1]

[2]

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6ova is ON HOLD  until Paper Publication
+==Crystal Structure of TYK2 with novel pyrrolidinone inhibitor==
+<StructureSection load='6ova' size='340' side='right'caption='[[6ova]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6ova]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6OVA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6OVA FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=N9G:6-({4-[(3S)-3-cyano-3-cyclopropyl-2-oxopyrrolidin-1-yl]pyridin-2-yl}amino)-N,N-dimethylpyridine-3-carboxamide'>N9G</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ova FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ova OCA], [http://pdbe.org/6ova PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ova RCSB], [http://www.ebi.ac.uk/pdbsum/6ova PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ova 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.
+== 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>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Herein we report an efficient method for the synthesis of a highly functionalized 2-pyrrolidinone, tert-butyl 3-cyano-3-cyclopropyl-2-oxopyrrolidine-4-carboxylate, from readily available starting materials. Utility of this compound was demonstrated in the synthesis of a novel series of macrocyclic Tyk2 inhibitors, leading to the identification of a potent and selective macrocyclic Tyk2 inhibitor (26).
-Authors: Skene, R.J., Hoffman, I.D.
+Efficient synthesis of tert-butyl 3-cyano-3-cyclopropyl-2-oxopyrrolidine-4-carboxylates: Highly functionalized 2-pyrrolidinone enabling access to novel macrocyclic Tyk2 inhibitors.,Sasaki Y, Tokuhara H, Ohba Y, Okabe A, Nakayama M, Nakagawa H, Skene R, Hoffman I, Zou H, Yoshida M Bioorg Med Chem Lett. 2020 Mar 1;30(5):126963. doi: 10.1016/j.bmcl.2020.126963., Epub 2020 Jan 13. PMID:31980341<ref>PMID:31980341</ref>
-Description: Crystal Structure of TYK2 with novel pyrrolidinone inhibitor
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Hoffman, I.D]]
+<div class="pdbe-citations 6ova" style="background-color:#fffaf0;"></div>
-[[Category: Skene, R.J]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Large Structures]]
+[[Category: Non-specific protein-tyrosine kinase]]
+[[Category: Hoffman, I D]]
+[[Category: Skene, R J]]
+[[Category: Complex]]
+[[Category: Inhibitor]]
+[[Category: Transferase-transferase inhibitor complex]]

6ova: Difference between revisions

Revision as of 04:18, 13 February 2020

Crystal Structure of TYK2 with novel pyrrolidinone inhibitor

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

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