6uwy

From Proteopedia

(Difference between revisions)

Revision as of 04:29, 13 February 2020

DYRK1A bound to a harmine derivative

Structural highlights

6uwy is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
NonStd Res:
Activity:	Dual-specificity kinase, with EC number 2.7.12.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[DYR1A_HUMAN] Defects in DYRK1A are the cause of mental retardation autosomal dominant type 7 (MRD7) [MIM:614104]. A disease characterized by primary microcephaly, severe mental retardation without speech, anxious autistic behavior, and dysmorphic features, including bitemporal narrowing, deep-set eyes, large simple ears, and a pointed nasal tip. Mental retardation is characterized by significantly below average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period.^[1]

Function

[DYR1A_HUMAN] May play a role in a signaling pathway regulating nuclear functions of cell proliferation. Phosphorylates serine, threonine and tyrosine residues in its sequence and in exogenous substrates.^[2]

Publication Abstract from PubMed

Recently, our group identified that harmine is able to induce beta-cell proliferation both in vitro and in vivo, mediated via the DYRK1A-NFAT pathway. Since, harmine suffers from lack of selectivity, both against other kinases and CNS off-targets, therefore, we sought to expand structure-activity relationships for harmine's DYRK1A activity, to enhance selectivity for off-targets, while retaining human beta-cell proliferation activity. We carried out optimization of the 9-N-position of harmine to synthesize 29 harmine-based analogs. Several novel inhibitors showed excellent DYRK1A inhibition and human beta-cell proliferation capability. An optimized DYRK1A inhibitor, 2-2c, was identified as a novel, efficacious in vivo lead candidate. 2-2c also demonstrates improved selectivity for kinases and CNS off-targets, as well as in vivo efficacy for beta-cell proliferation and regeneration at lower doses than harmine. Collectively, these findings demonstrate that 2-2c is a much-improved in vivo lead candidate as compared to harmine, for the treatment of diabetes.

Synthesis and Biological Validation of a Harmine-based, Central Nervous System (CNS)-Avoidant, Selective, Human beta-Cell Regenerative Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase A (DYRK1A) Inhibitor.,Kumar K, Wang P, Wilson J, Zlatanic V, Berrouet C, Khamrui S, Secor C, Swartz E, Lazarus MB, Sanchez R, Stewart AF, Garcia-Ocana A, DeVita RJ J Med Chem. 2020 Jan 31. doi: 10.1021/acs.jmedchem.9b01379. PMID:32003560^[3]

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

References

↑ van Bon BW, Hoischen A, Hehir-Kwa J, de Brouwer AP, Ruivenkamp C, Gijsbers AC, Marcelis CL, de Leeuw N, Veltman JA, Brunner HG, de Vries BB. Intragenic deletion in DYRK1A leads to mental retardation and primary microcephaly. Clin Genet. 2011 Mar;79(3):296-9. doi: 10.1111/j.1399-0004.2010.01544.x. PMID:21294719 doi:10.1111/j.1399-0004.2010.01544.x
↑ Shindoh N, Kudoh J, Maeda H, Yamaki A, Minoshima S, Shimizu Y, Shimizu N. Cloning of a human homolog of the Drosophila minibrain/rat Dyrk gene from "the Down syndrome critical region" of chromosome 21. Biochem Biophys Res Commun. 1996 Aug 5;225(1):92-9. PMID:8769099 doi:S0006-291X(96)91135-3
↑ Kumar K, Wang P, Wilson J, Zlatanic V, Berrouet C, Khamrui S, Secor C, Swartz E, Lazarus MB, Sanchez R, Stewart AF, Garcia-Ocana A, DeVita RJ. Synthesis and Biological Validation of a Harmine-based, Central Nervous System (CNS)-Avoidant, Selective, Human beta-Cell Regenerative Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase A (DYRK1A) Inhibitor. J Med Chem. 2020 Jan 31. doi: 10.1021/acs.jmedchem.9b01379. PMID:32003560 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b01379

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6uwy"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6uwy is ON HOLD  until Paper Publication
+==DYRK1A bound to a harmine derivative==
+<StructureSection load='6uwy' size='340' side='right'caption='[[6uwy]], [[Resolution|resolution]] 2.95&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6uwy]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6UWY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6UWY FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=QKG:4-(7-methoxy-1-methyl-9H-beta-carbolin-9-yl)butanamide'>QKG</scene></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='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dual-specificity_kinase Dual-specificity kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.12.1 2.7.12.1] </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=6uwy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uwy OCA], [http://pdbe.org/6uwy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6uwy RCSB], [http://www.ebi.ac.uk/pdbsum/6uwy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6uwy ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[[http://www.uniprot.org/uniprot/DYR1A_HUMAN DYR1A_HUMAN]] Defects in DYRK1A are the cause of mental retardation autosomal dominant type 7 (MRD7) [MIM:[http://omim.org/entry/614104 614104]]. A disease characterized by primary microcephaly, severe mental retardation without speech, anxious autistic behavior, and dysmorphic features, including bitemporal narrowing, deep-set eyes, large simple ears, and a pointed nasal tip. Mental retardation is characterized by significantly below average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period.<ref>PMID:21294719</ref>
+== Function ==
+[[http://www.uniprot.org/uniprot/DYR1A_HUMAN DYR1A_HUMAN]] May play a role in a signaling pathway regulating nuclear functions of cell proliferation. Phosphorylates serine, threonine and tyrosine residues in its sequence and in exogenous substrates.<ref>PMID:8769099</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Recently, our group identified that harmine is able to induce beta-cell proliferation both in vitro and in vivo, mediated via the DYRK1A-NFAT pathway. Since, harmine suffers from lack of selectivity, both against other kinases and CNS off-targets, therefore, we sought to expand structure-activity relationships for harmine's DYRK1A activity, to enhance selectivity for off-targets, while retaining human beta-cell proliferation activity. We carried out optimization of the 9-N-position of harmine to synthesize 29 harmine-based analogs. Several novel inhibitors showed excellent DYRK1A inhibition and human beta-cell proliferation capability. An optimized DYRK1A inhibitor, 2-2c, was identified as a novel, efficacious in vivo lead candidate. 2-2c also demonstrates improved selectivity for kinases and CNS off-targets, as well as in vivo efficacy for beta-cell proliferation and regeneration at lower doses than harmine. Collectively, these findings demonstrate that 2-2c is a much-improved in vivo lead candidate as compared to harmine, for the treatment of diabetes.
-Authors:
+Synthesis and Biological Validation of a Harmine-based, Central Nervous System (CNS)-Avoidant, Selective, Human beta-Cell Regenerative Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase A (DYRK1A) Inhibitor.,Kumar K, Wang P, Wilson J, Zlatanic V, Berrouet C, Khamrui S, Secor C, Swartz E, Lazarus MB, Sanchez R, Stewart AF, Garcia-Ocana A, DeVita RJ J Med Chem. 2020 Jan 31. doi: 10.1021/acs.jmedchem.9b01379. PMID:32003560<ref>PMID:32003560</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 6uwy" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Dual-specificity kinase]]
+[[Category: Large Structures]]
+[[Category: Khamrui, S]]
+[[Category: Lazarus, M B]]
+[[Category: Kinase]]
+[[Category: Transferase]]
+[[Category: Transferase-transferase inhibitor complex]]

6uwy

From Proteopedia

Revision as of 04:29, 13 February 2020

DYRK1A bound to a harmine derivative

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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