Gold‐Catalyzed C–S Aryl‐Group Transfer in Zinc Finger Proteins

Abstract

Reaction of the Au-C N chelate [Au(bnpy)Cl ] with the full-length zinc finger (ZnF; ZnCys His) of HIV nucleocapsid protein NCp7 results in C-S aryl transfer from the Au organometallic species to a cysteine of the ZnF. The reaction is general and occurs even for finger 3 of the transcription factor Sp1, containing a ZnCys His coordination sphere. This reaction is the first demonstration of group transfer from a coordination compound to biologically important zinc fingers, and is especially noteworthy for the ZnCys His transcription factors. The work expands the corpus of organometallic species which can efficiently modify biomolecules through C-atom transfer. The electronic features of the gold compound leading to this unexpected reaction were explored by X-ray absorption spectroscopy.

Role of Gold in Inflammation and Tristetraprolin Activity

“…[1a, 3] We took this approacha nd isolated ac onstruct of TTP called TTP-2D, which contains the protein'st wo CCCH domains.W eh ave previously reported the cloning, overexpression and purification of TTP-2D, and demonstrated that it is highly soluble, binds and folds aroundz inc, and functions (selectively recognize AU-rich mRNA targets)( Figure 1A,B). [13b, 19] Au III terpy is soluble in aqueous solution and it exhibits rich spectroscopy (charge-transfer bands) that are sensitive to metal coordination, allowing for reactivity to be followed optically.M oreover,t here are severalr ecent reports of the interaction of gold complexes,i ncluding Au III terpy,w ith ZF peptides, including Cys 4 "zinc ribbon"s ites, [13b] Cys 2 HisCys "zinc knuckle", [12,14,20] Cys 2 HisCys( PARP-1), [13,21] andC ys 2 His 2 classical ZF, [12a,c, 14, 22] and consensus peptide1(Cys 2 His 2 ). [13b, 19] Au III terpy is soluble in aqueous solution and it exhibits rich spectroscopy (charge-transfer bands) that are sensitive to metal coordination, allowing for reactivity to be followed optically.M oreover,t here are severalr ecent reports of the interaction of gold complexes,i ncluding Au III terpy,w ith ZF peptides, including Cys 4 "zinc ribbon"s ites, [13b] Cys 2 HisCys "zinc knuckle", [12,14,20] Cys 2 HisCys( PARP-1), [13,21] andC ys 2 His 2 classical ZF, [12a,c, 14, 22] and consensus peptide1(Cys 2 His 2 ).…”

“…[6] This property has led to TTP being dubbed a" master regulator" of inflammation. [11] However,t he biochemical mechanism by which goldf unctionsa sa na nti-inflammatory, and particularly which proteins are targeted by gold are not well understood.There are several reports that gold complexes can target thiol-rich ZFs and peptides including the HIV-nucleocapsidp 7p rotein (HIVNCp7), [12] poly(adenosine diphosphate (ADP)-ribose) polymerase 1( PARP-1), [13] Sp1 transcriptionf actor, [12a,c, 14] and model ZF peptides, [13b, 15] as well as extensive work by both the Farrell and Casini laboratories in the design of gold complexes to chemically modify ZF sites. [8] Given its major role in regulating inflammation, there is ag rowing interest in modulating TTP function am eanst oc ontrol inflammatory response.…”

“…[10] Gold has long been known to exhibit anti-inflammatory properties, and there is currently an FDA approved gold anti-inflammatory drug, Auranofin, indicated to treat rheumatoid arthritis. [11] However,t he biochemical mechanism by which goldf unctionsa sa na nti-inflammatory, and particularly which proteins are targeted by gold are not well understood.There are several reports that gold complexes can target thiol-rich ZFs and peptides including the HIV-nucleocapsidp 7p rotein (HIVNCp7), [12] poly(adenosine diphosphate (ADP)-ribose) polymerase 1( PARP-1), [13] Sp1 transcriptionf actor, [12a,c, 14] and model ZF peptides, [13b, 15] as well as extensive work by both the Farrell and Casini laboratories in the design of gold complexes to chemically modify ZF sites. [12a, 16] How gold targets TTP is not known;h owever,a sT TP is at hiol-rich ZF with six cysteine residues, we reasoned that the reported modulation of the NF-kBp athway by gold may involver eactivity of gold with TTP.…”

Selective Targeting of the Zinc Finger Domain of HIV Nucleocapsid Protein NCp7 with Ruthenium Complexes

“…Several metal compounds, such as Pt II , Au III , As III agents, have shown inhibition activity to NCp7. These metal complexes bind to NCp7 through coordination substitution, resulting in zinc‐ejection from the protein by thiolate metalation.…”

Cyclometalated AuIII Complexes for Cysteine Arylation in Zinc Finger Protein Domains: towards Controlled Reductive Elimination

“…[13] The Cys arylation was observed by mass spectrometry after 48 hi ncubation with the peptide. [13] The Cys arylation was observed by mass spectrometry after 48 hi ncubation with the peptide.…”