5A4T

DYRK1A IN COMPLEX WITH NITRILE BENZOTHIAZOLE FRAGMENT

5A4T の概要

• エントリーDOI: 10.2210/pdb5a4t/pdb
• 関連するPDBエントリー: 5A4E 5A4L 5A4Q 5A54
• 分子名称: DUAL SPECIFICITY TYROSINE-PHOSPHORYLATION- REGULATED KINASE 1A, N-(6-CYANO-3H-1,3-BENZOTHIAZOL-2-YLIDENE)ETHANAMIDE (3 entities in total)
• 機能のキーワード: transferase
• 由来する生物種: HOMO SAPIENS (HUMAN)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 171484.96

構造登録者

Rothweiler, U. (登録日: 2015-06-15, 公開日: 2016-06-29, 最終更新日: 2024-10-16)

主引用文献

Rothweiler, U.,Stensen, W.,Brandsdal, B.O.,Isaksson, J.,Leeson, F.A.,Eugh, R.A.,Mjoen Svendsen, J.S.
Probing the ATP-Binding Pocket of Protein Kinase Dyrk1A with Benzothiazole Fragment Molecules
J.Med.Chem., 59:9814-, 2016

PubMed Abstract: 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.

PubMed: 27736065
DOI: 10.1021/ACS.JMEDCHEM.6B01086

実験手法

X-RAY DIFFRACTION (2.15 Å)