7CGD

Silver-bound E.coli malate dehydrogenase

7CGD の概要

• エントリーDOI: 10.2210/pdb7cgd/pdb
• 分子名称: Malate dehydrogenase, SILVER ION (3 entities in total)
• 機能のキーワード: malate dehydrogenase, silver, tca cycle, metal binding protein
• 由来する生物種: Escherichia coli K-12
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 132381.20

構造登録者

Wang, H.,Wang, M.,Sun, H. (登録日: 2020-07-01, 公開日: 2020-09-23, 最終更新日: 2023-11-29)

主引用文献

Wang, H.,Yang, X.,Wang, M.,Hu, M.,Xu, X.,Yan, A.,Hao, Q.,Li, H.,Sun, H.
Atomic differentiation of silver binding preference in protein targets: Escherichia coli malate dehydrogenase as a paradigm.
Chem Sci, 11:11714-11719, 2020

PubMed Abstract: Understanding how metallodrugs interact with their protein targets is of vital importance for uncovering their molecular mode of actions as well as overall pharmacological/toxicological profiles, which in turn facilitates the development of novel metallodrugs. Silver has been used as an antimicrobial agent since antiquity, yet there is limited knowledge about silver-binding proteins. Given the multiple dispersed cysteine residues and histidine-methionine pairs, malate dehydrogenase (MDH) represents an excellent model to investigate silver coordination chemistry as well as its targeting sites in enzymes. We show by systematic biochemical characterizations that silver ions (Ag) bind MDH at multiple sites including three cysteine-containing sites. By X-ray crystallography, we unravel the binding preference of Ag to multiple binding sites in MDH, Cys113 > Cys251 > Cys109 > Met227. Silver exhibits preferences to the donor atoms and residues in the order of S > N > O and Cys > Met > His > Lys > Val, respectively, in MDH. For the first time, we report the coordination of silver to a lysine in proteins. Besides, we also observed argentophilic interactions (Ag⋯Ag, 2.7 to 3.3 Å) between two silver ions coordinating to one thiolate. Combined with site-directed mutagenesis and an enzymatic activity test, we unveil that the binding of Ag to the site IV (His177-Ag-Met227 site) plays a vital role in Ag-mediated MDH inactivation. This work stands as the first unusual and explicit study of silver binding preference to multiple binding sites in its authentic protein target at the atomic resolution. These findings enrich our knowledge on the biocoordination chemistry of silver(i), which in turn facilitates the prediction of the unknown silver-binding proteins and extends the pharmaceutical potentials of metal-based drugs.

PubMed: 34123202
DOI: 10.1039/d0sc04151c

実験手法

X-RAY DIFFRACTION (2.06 Å)