5RXO

INPP5D PanDDA analysis group deposition -- Crystal Structure of the phosphatase and C2 domains of SHIP1 in complex with Z68299550

5RXO の概要

• エントリーDOI: 10.2210/pdb5rxo/pdb
• Group deposition: INPP5D PanDDA analysis group deposition (G_1002180)
• 分子名称: Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1, 3-chloro-N-(1-hydroxy-2-methylpropan-2-yl)benzamide, DIMETHYL SULFOXIDE, ... (4 entities in total)
• 機能のキーワード: sgc - diamond i04-1 fragment screening, pandda, xchemexplorer, ship1, alzheimers, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 53339.66

構造登録者

Bradshaw, W.J.,Newman, J.A.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Gileadi, O. (登録日: 2020-10-30, 公開日: 2020-11-11, 最終更新日: 2024-02-14)

主引用文献

Bradshaw, W.J.,Kennedy, E.C.,Moreira, T.,Smith, L.A.,Chalk, R.,Katis, V.L.,Benesch, J.L.P.,Brennan, P.E.,Murphy, E.J.,Gileadi, O.
Regulation of inositol 5-phosphatase activity by the C2 domain of SHIP1 and SHIP2.
Structure, 2024

PubMed Abstract: SHIP1, an inositol 5-phosphatase, plays a central role in cellular signaling. As such, it has been implicated in many conditions. Exploiting SHIP1 as a drug target will require structural knowledge and the design of selective small molecules. We have determined apo, and magnesium and phosphate-bound structures of the phosphatase and C2 domains of SHIP1. The C2 domains of SHIP1 and the related SHIP2 modulate the activity of the phosphatase domain. To understand the mechanism, we performed activity assays, hydrogen-deuterium exchange mass spectrometry, and molecular dynamics on SHIP1 and SHIP2. Our findings demonstrate that the influence of the C2 domain is more pronounced for SHIP2 than SHIP1. We determined 91 structures of SHIP1 with fragments bound, with some near the interface between the two domains. We performed a mass spectrometry screen and determined four structures with covalent fragments. These structures could act as starting points for the development of potent, selective probes.

PubMed: 38309262
DOI: 10.1016/j.str.2024.01.005

実験手法

X-RAY DIFFRACTION (1.71 Å)