Identification of Labile Zn Sites in Drug-Target Proteins

Lee, Yu-Ming; Wang, Yiting; Duh, Yulander; Yuan, Hanna S.; Lim, Carmay

doi:10.1021/ja406300c

Cited by 20 publications

(22 citation statements)

References 40 publications

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“…We then used these guidelines to identify drug-target proteins containing labile structural Zn-sites. 8,10 To circumvent toxicity due to undesirable targeting of essential human proteins, we had proposed using clinically safe (FDA-approved or in phase II/III clinical trials) Zn-ejecting agents that do not affect crucial host proteins (ESI Table S1 †) to target putative labile Zn-sites in viral proteins. 8 We showed that disulram, an anti-alcoholism drug, can eject Zn 2+ from the predicted labile Zn-Cys 4 site in the hepatitis C virus NS5A protein, inhibiting viral replication, and that inhibition was enhanced when disulram was combined with interferon-a.…”

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confidence: 99%

Multi-targeting of functional cysteines in multiple conserved SARS-CoV-2 domains by clinically safe Zn-ejectors

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Multi-targeting of functional cysteines in multiple conserved SARS-CoV-2 domains by clinically safe Zn-ejectors

et al. 2020

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“…via its zinc-finger like motif, we tested three covalent inhibitors with thiol-reactive groups. Ebselen, disulfiram and auranofin have the potential to interact with zinc fingers, including via zinc ejection with consequent protein destabilization [69,70,79,80]. Both ebselen and auranofin are reported have some antimicrobial properties [81], ebselen is in clinical trials for a variety of conditions, ranging from stroke to bipolar disorder [82], and auranofin is used for treatment of rheumatoid arthritis [83].…”

Section: Discussionmentioning

confidence: 99%

Structural and mechanistic insights into the Artemis endonuclease and strategies for its inhibition

Yosaatmadja

Baddock

Newman

et al. 2021

Preprint

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Artemis (DCLRE1C) is an endonuclease that plays a key role in development of B- and T-lymphocytes and in DNA double-strand break repair by non-homologous end-joining (NHEJ). Artemis is phosphorylated by DNA-PKcs and acts to open DNA hairpin intermediates generated during V(D)J and class-switch recombination. Consistently, Artemis deficiency leads to radiosensitive congenital severe immune deficiency (RS-SCID). Artemis belongs to a structural superfamily of nucleases that contain conserved metallo-β-lactamase (MBL) and β-CASP (CPSF-Artemis-SNM1-Pso2) domains. Here, we present crystal structures of the catalytic domain of wild type and variant forms of Artemis that cause RS-SCID Omenn syndrome. The truncated catalytic domain of the Artemis is a constitutively active enzyme that with similar activity to a phosphorylated full-length protein. Our structures help explain the basis of the predominantly endonucleolytic activity of Artemis, which contrast with the predominantly exonuclease activity of the closely related SNM1A and SNM1B nucleases. The structures also reveal a second metal binding site in its β-CASP domain that is unique to Artemis. By combining our structural data that from a recently reported structure we were able model the interaction of Artemis with DNA substrates. Moreover, co-crystal structures with inhibitors indicate the potential for structure-guided development of inhibitors.

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“…In addition we found that dithiopyridine, an inhibitor of ZBTB25, blocked the recruitment of HDAC1 silencing complex to IL-12B promoter. Dithiopyridine is a zinc ejector that inactivates the functionality of zinc finger domain (Lee et al, 2013), and has been used for the inactivation of the zinc-finger nucleocapsid of HIV-1 (Arthur et al, 1998). We further found that knocking down of ZBTB25 disrupts the recruitment of HDAC1 to the promoter of IL-12B promoter and subsequently derepressing the gene expression.…”

Section: Discussionmentioning

confidence: 99%

Transcription repressor protein ZBTB25 interacts with HDAC1 in macrophages infected withMycobacterium tuberculosis,and its inhibition leads to autophagy and killing of the intracellular pathogen

Madhavan

Arun

Pushparajan

et al. 2020

Preprint

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Downregulation of host gene expression is one of the key strategies adopted by intracellular pathogens such as Mycobacterium tuberculosis (MTB) for their survival and subsequent pathogenesis. In a previous study, we have shown that HDAC1 levels go up in macrophages infected with MTB and it hypoacetylates histone H3 at the promoter of IL-12B gene leading to its downregulation. Here we show that after infection with MTB, the levels of the phosphorylated form of HDAC1 increase significantly in macrophages. Employing immunoprecipitation and LC-MS/MS, we found transcriptional repressor protein ZBTB25 associates with HDAC1 silencing complex along with transcriptional corepressor Sin3a. By chromatin immunoprecipitation and PCR analyses, we found that phosphorylated HDAC1, Sin3a, and ZBTB25 are recruited to the promoter of IL-12B to downregulate its expression in infected macrophages. Knocking down of ZBTB25 enhanced release of IL-12p40 from infected macrophages. Interestingly, the treatment of infected macrophages with CI994 (inhibitor of HDAC1) or dithiopyridine (inhibitor of ZBTB25) promoted the colocalization of LC3 (microtubule-associated protein 1A/1B-light chain 3, a marker for autophagy) and MTB in autophagosomes. Induction of autophagy resulted in the killing of intracellular MTB.Enhanced phosphorylation of JAK2 and STAT4 was observed in macrophages upon CI994 and dithiopyridine treatment, and inhibition of JAK2/STAT4 negated the killing of intracellular mycobacteria suggesting a possible role of these proteins in the autophagymediated killing of intracellular MTB.

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Identification of Labile Zn Sites in Drug-Target Proteins

Cited by 20 publications

References 40 publications

Multi-targeting of functional cysteines in multiple conserved SARS-CoV-2 domains by clinically safe Zn-ejectors

Multi-targeting of functional cysteines in multiple conserved SARS-CoV-2 domains by clinically safe Zn-ejectors

Structural and mechanistic insights into the Artemis endonuclease and strategies for its inhibition

Transcription repressor protein ZBTB25 interacts with HDAC1 in macrophages infected withMycobacterium tuberculosis,and its inhibition leads to autophagy and killing of the intracellular pathogen

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