5a4e

From Proteopedia

(Difference between revisions)

Revision as of 09:16, 30 January 2019

DYRK1A in complex with methoxy benzothiazole fragment

Structural highlights

5a4e 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:
Related:	5a3x, 5a4l, 5a4q, 5a4t, 5a54
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

DYRK1A has emerged as a potential target for therapies of Alzheimer's disease using small molecules. On the basis of the observation of selective DYRK1A inhibition by firefly d-luciferin, we have explored static and dynamic structural properties of fragment sized variants of the benzothiazole scaffold with respect to DYRK1A using X-ray crystallography and NMR techniques. The compounds have excellent ligand efficiencies and show a remarkable diversity of binding modes in dynamic equilibrium. Binding geometries are determined in part by interactions often considered "weak", including "orthogonal multipolar" types represented by, for example, F-CO, sulfur-aromatic, and halogen-aromatic interactions, together with hydrogen bonds that are modulated by variation of electron withdrawing groups. These studies show how the benzothiazole scaffold is highly promising for the development of therapeutic DYRK1A inhibitors. In addition, the subtleties of the binding interactions, including dynamics, show how full structural studies are required to fully interpret the essential physical determinants of binding.

Probing the ATP-Binding Pocket of Protein Kinase DYRK1A with Benzothiazole Fragment Molecules.,Rothweiler U, Stensen W, Brandsdal BO, Isaksson J, Leeson FA, Engh RA, Svendsen JS J Med Chem. 2016 Nov 10;59(21):9814-9824. Epub 2016 Oct 21. PMID:27736065^[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
↑ Rothweiler U, Stensen W, Brandsdal BO, Isaksson J, Leeson FA, Engh RA, Svendsen JS. Probing the ATP-Binding Pocket of Protein Kinase DYRK1A with Benzothiazole Fragment Molecules. J Med Chem. 2016 Nov 10;59(21):9814-9824. Epub 2016 Oct 21. PMID:27736065 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b01086

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/5a4e"

Categories: Dual-specificity kinase | Human | Rothweiler, U | Transferase

@@ Line 1: / Line 1: @@
-==DYRK1A IN COMPLEX WITH METHOXY BENZOTHIAZOL FRAGMENT==
+==DYRK1A in complex with methoxy benzothiazole fragment==
 <StructureSection load='5a4e' size='340' side='right' caption='[[5a4e]], [[Resolution|resolution]] 2.68&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5a4e]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5A4E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5A4E FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5a4e]] 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=5A4E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5A4E FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7QQ:N-(5-METHOXY-1,3-BENZOTHIAZOL-2-YL)ETHANAMIDE'>7QQ</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>
@@ Line 28: / Line 28: @@
 </StructureSection>
 [[Category: Dual-specificity kinase]]
+[[Category: Human]]
 [[Category: Rothweiler, U]]
 [[Category: Transferase]]

5a4e

From Proteopedia

Revision as of 09:16, 30 January 2019

DYRK1A in complex with methoxy benzothiazole fragment

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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