5MQ5

A protease-resistant N24S Escherichia coli Asparaginase mutant with outstanding stability and enhanced anti-leukaemic activity

5MQ5 の概要

• エントリーDOI: 10.2210/pdb5mq5/pdb
• 分子名称: L-asparaginase 2, ASPARTIC ACID (3 entities in total)
• 機能のキーワード: l-asparaginase, amidohydrolase, chemotherapeutic drug, hydrolase
• 由来する生物種: Escherichia coli
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 142247.05

構造登録者

Maggi, M.,Mittelman, S.D.,Parmentier, J.H.,Whitmire, J.M.,Merrell, D.S.,Scotti, C. (登録日: 2016-12-20, 公開日: 2017-11-15, 最終更新日: 2024-11-06)

主引用文献

Maggi, M.,Mittelman, S.D.,Parmentier, J.H.,Colombo, G.,Meli, M.,Whitmire, J.M.,Merrell, D.S.,Whitelegge, J.,Scotti, C.
A protease-resistant Escherichia coli asparaginase with outstanding stability and enhanced anti-leukaemic activity in vitro.
Sci Rep, 7:14479-14479, 2017

PubMed Abstract: L-Asparaginases (ASNases) have been used as first line drugs for paediatric Acute Lymphoblastic Leukaemia (ALL) treatment for more than 40 years. Both the Escherichia coli (EcAII) and Erwinia chrysanthemi (ErAII) type II ASNases currently used in the clinics are characterized by high in vivo instability, short half-life and the requirement of several administrations to obtain a pharmacologically active concentration. Moreover, they are sensitive to proteases (cathepsin B and asparagine endopeptidase) that are over-expressed by resistant leukaemia lymphoblasts, thereby impairing drug activity and pharmacokinetics. Herein, we present the biochemical, structural and in vitro antiproliferative characterization of a new EcAII variant, N24S. The mutant shows completely preserved asparaginase and glutaminase activities, long-term storage stability, improved thermal parameters, and outstanding resistance to proteases derived from leukaemia cells. Structural analysis demonstrates a modification in the hydrogen bond network related to residue 24, while Normal Mode-based geometric Simulation and Molecular Dynamics predict a general rigidification of the monomer as compared to wild-type. These improved features render N24S a potential alternative treatment to reduce the number of drug administrations in vivo and to successfully address one of the major current challenges of ALL treatment: spontaneous, protease-dependent and immunological inactivation of ASNase.

PubMed: 29101342
DOI: 10.1038/s41598-017-15075-4

実験手法

X-RAY DIFFRACTION (1.6 Å)