6t6a

From Proteopedia

(Difference between revisions)

Revision as of 07:36, 30 September 2020

Crystal structure of DYRK1A complexed with KuFal319 (compound 11)

Structural highlights

6t6a is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
NonStd Res:
Gene:	DYRK1A, DYRK, MNB, MNBH (HUMAN)
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

Since hyperactivity of the protein kinase DYRK1A is linked to several neurodegenerative disorders, DYRK1A inhibitors have been suggested as potential therapeutics for Down syndrome and Alzheimer's disease. Most published inhibitors to date suffer from low selectivity against related kinases or from unfavorable physicochemical properties. In order to identify DYRK1A inhibitors with improved properties, a series of new chemicals based on [b]-annulated halogenated indoles were designed, synthesized, and evaluated for biological activity. Analysis of crystal structures revealed a typical type-I binding mode of the new inhibitor 4-chlorocyclohepta[b]indol-10(5H)-one in DYRK1A, exploiting mainly shape complementarity for tight binding. Conversion of the DYRK1A inhibitor 8-chloro-1,2,3,9-tetrahydro-4H-carbazol-4-one into a corresponding Mannich base hydrochloride improved the aqueous solubility but abrogated kinase inhibitory activity.

[b]-Annulated Halogen-Substituted Indoles as Potential DYRK1A Inhibitors.,Lechner C, Flasshoff M, Falke H, Preu L, Loaec N, Meijer L, Knapp S, Chaikuad A, Kunick C Molecules. 2019 Nov 13;24(22). pii: molecules24224090. doi:, 10.3390/molecules24224090. PMID:31766108^[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
↑ Lechner C, Flasshoff M, Falke H, Preu L, Loaec N, Meijer L, Knapp S, Chaikuad A, Kunick C. [b]-Annulated Halogen-Substituted Indoles as Potential DYRK1A Inhibitors. Molecules. 2019 Nov 13;24(22). pii: molecules24224090. doi:, 10.3390/molecules24224090. PMID:31766108 doi:http://dx.doi.org/10.3390/molecules24224090

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/6t6a"

@@ Line 3: / Line 3: @@
 <StructureSection load='6t6a' size='340' side='right'caption='[[6t6a]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6t6a]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6T6A OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6T6A FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6t6a]] is a 4 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=6T6A OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6T6A FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MLW:4-chloranyl-5~{H}-cyclohepta[b]indol-10-one'>MLW</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MLW:4-chloranyl-5~{H}-cyclohepta[b]indol-10-one'>MLW</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DYRK1A, DYRK, MNB, MNBH ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6t6a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6t6a OCA], [http://pdbe.org/6t6a PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6t6a RCSB], [http://www.ebi.ac.uk/pdbsum/6t6a PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6t6a ProSAT]</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=6t6a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6t6a OCA], [http://pdbe.org/6t6a PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6t6a RCSB], [http://www.ebi.ac.uk/pdbsum/6t6a PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6t6a ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 22: / Line 23: @@
 </div>
 <div class="pdbe-citations 6t6a" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Dual specificity tyrosine-phosphorylation-regulated kinase|Dual specificity tyrosine-phosphorylation-regulated kinase]]
 == References ==
 <references/>
@@ Line 27: / Line 31: @@
 </StructureSection>
 [[Category: Dual-specificity kinase]]
+[[Category: Human]]
 [[Category: Large Structures]]
 [[Category: Arrowsmith, C H]]

6t6a

From Proteopedia

Revision as of 07:36, 30 September 2020

Crystal structure of DYRK1A complexed with KuFal319 (compound 11)

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox