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Article: Atomic differentiation of silver binding preference in protein targets: Escherichia coli malate dehydrogenase as a paradigm

TitleAtomic differentiation of silver binding preference in protein targets: Escherichia coli malate dehydrogenase as a paradigm
Authors
Issue Date2020
PublisherRoyal Society of Chemistry: Open Access Journals. The Journal's web site is located at http://www.rsc.org/publishing/journals/sc/About.asp
Citation
Chemical Science, 2020, v. 11 n. 43, p. 11714-11719 How to Cite?
AbstractUnderstanding 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, Escherichia coli malate dehydrogenase (EcMDH) 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 EcMDH at multiple sites including three cysteine-containing sites. By X-ray crystallography, we unravel the binding preference of Ag+ to multiple binding sites in EcMDH, i.e., 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 EcMDH. 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.
Persistent Identifierhttp://hdl.handle.net/10722/293214
ISSN
2020 Impact Factor: 9.825
2015 SCImago Journal Rankings: 4.974
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorWang, H-
dc.contributor.authorYang, X-
dc.contributor.authorWang, M-
dc.contributor.authorHu, M-
dc.contributor.authorXu, X-
dc.contributor.authorYan, A-
dc.contributor.authorHao, Q-
dc.contributor.authorLi, H-
dc.contributor.authorSun, H-
dc.date.accessioned2020-11-23T08:13:29Z-
dc.date.available2020-11-23T08:13:29Z-
dc.date.issued2020-
dc.identifier.citationChemical Science, 2020, v. 11 n. 43, p. 11714-11719-
dc.identifier.issn2041-6520-
dc.identifier.urihttp://hdl.handle.net/10722/293214-
dc.description.abstractUnderstanding 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, Escherichia coli malate dehydrogenase (EcMDH) 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 EcMDH at multiple sites including three cysteine-containing sites. By X-ray crystallography, we unravel the binding preference of Ag+ to multiple binding sites in EcMDH, i.e., 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 EcMDH. 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.-
dc.languageeng-
dc.publisherRoyal Society of Chemistry: Open Access Journals. The Journal's web site is located at http://www.rsc.org/publishing/journals/sc/About.asp-
dc.relation.ispartofChemical Science-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleAtomic differentiation of silver binding preference in protein targets: Escherichia coli malate dehydrogenase as a paradigm-
dc.typeArticle-
dc.identifier.emailWang, H: wanghaib@hku.hk-
dc.identifier.emailHu, M: hu99525@hku.hk-
dc.identifier.emailYan, A: ayan8@hku.hk-
dc.identifier.emailHao, Q: qhao@hku.hk-
dc.identifier.emailLi, H: hylichem@hku.hk-
dc.identifier.emailSun, H: hsun@hku.hk-
dc.identifier.authorityYan, A=rp00823-
dc.identifier.authorityHao, Q=rp01332-
dc.identifier.authoritySun, H=rp00777-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1039/D0SC04151C-
dc.identifier.scopuseid_2-s2.0-85096039640-
dc.identifier.hkuros318941-
dc.identifier.volume11-
dc.identifier.issue43-
dc.identifier.spage11714-
dc.identifier.epage11719-
dc.identifier.isiWOS:000588192000030-
dc.publisher.placeUnited Kingdom-

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