7OV8

Crystal structure of pig purple acid phosphatase in complex with 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) and glycerol

7OV8 の概要

• エントリーDOI: 10.2210/pdb7ov8/pdb
• 関連するPDBエントリー: 7OV2 7OV3
• 分子名称: Tartrate-resistant acid phosphatase type 5, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, ... (10 entities in total)
• 機能のキーワード: purple acid phosphatase, metallohydrolases, osteoporosis, fragment-based drug design, metal binding protein, hydrolase
• 由来する生物種: Sus scrofa (Pig)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 40911.04

構造登録者

Feder, D.,McGeary, R.P.,Guddat, L.W.,Schenk, G. (登録日: 2021-06-14, 公開日: 2022-03-23, 最終更新日: 2024-10-09)

主引用文献

Feder, D.,Mohd-Pahmi, S.H.,Hussein, W.M.,Guddat, L.W.,McGeary, R.P.,Schenk, G.
Rational Design of Potent Inhibitors of a Metallohydrolase Using a Fragment-Based Approach.
Chemmedchem, 16:3342-3359, 2021

PubMed Abstract: Metallohydrolases form a large group of enzymes that have fundamental importance in a broad range of biological functions. Among them, the purple acid phosphatases (PAPs) have gained attention due to their crucial role in the acquisition and use of phosphate by plants and also as a promising target for novel treatments of bone-related disorders and cancer. To date, no crystal structure of a mammalian PAP with drug-like molecules bound near the active site is available. Herein, we used a fragment-based design approach using structures of a mammalian PAP in complex with the Maybridge fragment CC063346, the amino acid L-glutamine and the buffer molecule HEPES, as well as various solvent molecules to guide the design of highly potent and efficient mammalian PAP inhibitors. These inhibitors have improved aqueous solubility when compared to the clinically most promising PAP inhibitors available to date. Furthermore, drug-like fragments bound in newly discovered binding sites mapped out additional scaffolds for further inhibitor discovery, as well as scaffolds for the design of inhibitors with novel modes of action.

PubMed: 34331400
DOI: 10.1002/cmdc.202100486

実験手法

X-RAY DIFFRACTION (2.3 Å)