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Article ; Online: Not All Binding Sites Are Equal: Site Determination and Folding State Analysis of Gas-Phase Protein-Metallodrug Adducts.

Eade, Liam / Sullivan, Matthew P / Allison, Timothy M / Goldstone, David C / Hartinger, Christian G

Chemistry (Weinheim an der Bergstrasse, Germany)

2024 , Page(s) e202400268

Abstract: Modern approaches in metallodrug research focus on compounds that bind protein targets rather than DNA. However, the identification of protein targets and binding sites is challenging. Using intact mass spectrometry and proteomics, we investigated the ... ...

Abstract	Modern approaches in metallodrug research focus on compounds that bind protein targets rather than DNA. However, the identification of protein targets and binding sites is challenging. Using intact mass spectrometry and proteomics, we investigated the binding of the antimetastatic agent RAPTA-C to the model proteins ubiquitin, cytochrome c, lysozyme, and myoglobin. Binding to cytochrome c and lysozyme was negligible. However, ubiquitin bound up to three Ru moieties, two of which were localized at Met1 and His68 as [Ru(cym)], and [Ru(cym)] or [Ru(cym)(PTA)] adducts, respectively. Myoglobin bound up to four [Ru(cym)(PTA)] moieties and five sites were identified at His24, His36, His64, His81/82 and His113. Collision-induced unfolding (CIU) studies via ion-mobility mass spectrometry allowed measuring protein folding as a function of collisional activation. CIU of protein-RAPTA-C adducts showed binding of [Ru(cym)] to Met1 caused a significant compaction of ubiquitin, likely from N-terminal S-Ru-N chelation, while binding of [Ru(cym)(PTA)] to His residues of ubiquitin or myoglobin induced a smaller effect. Interestingly, the folded state of ubiquitin formed by His functionalization was more stable than Met1 metalation. The data suggests that selective metalation of amino acids at different positions on the protein impacts the conformation and potentially the biological activity of anticancer compounds.
Language	English
Publishing date	2024-03-12
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1478547-X
ISSN	1521-3765 ; 0947-6539
ISSN (online)	1521-3765
ISSN	0947-6539
DOI	10.1002/chem.202400268
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Article ; Online: Mapping the interaction between Trim28 and the KRAB domain at the center of Trim28 silencing of endogenous retroviruses.

Taka, Jamie R H / Sun, Yunyuan / Goldstone, David C

Protein science : a publication of the Protein Society

2022 Volume 31, Issue 10, Page(s) e4436

Abstract: Transcription of endogenous retroviral elements are tightly regulated during development by members of the KRAB-containing zinc finger proteins (KRAB-ZFPs) and the co-repressor Trim28 (also known as Kap-1 or Tif1β). KRAB-ZFPs form the largest family of ... ...

Abstract	Transcription of endogenous retroviral elements are tightly regulated during development by members of the KRAB-containing zinc finger proteins (KRAB-ZFPs) and the co-repressor Trim28 (also known as Kap-1 or Tif1β). KRAB-ZFPs form the largest family of transcription regulators in mammals and initiate transcriptional silencing by tethering Trim28 to a target locus. Subsequently, Trim28 recruits chromatin modifying effectors resulting in the formation of heterochromatin. In the present study, we identify surface exposed residues on the central six turns of the Trim28 coiled-coil region forming the binding interface for the KRAB domain. Using AlphaFold2 (AF2) we provide high confidence models of the interface between Trim28 and the KRAB domain and identified leucine 301 on each chain of the Trim28 monomer to act as a pin extending into a hydrophobic pocket on the KRAB domain surface. Site directed mutations in the Trim28-KRAB binding interface abolished binding to the KRAB domain. Our work provides a detailed understanding of the specific interactions between the KRAB domain and the Trim28 coiled-coil and how this interaction may be regulated during silencing events.
MeSH term(s)	Animals ; Chromatin ; Co-Repressor Proteins/genetics ; Endogenous Retroviruses/metabolism ; Furylfuramide ; Heterochromatin ; Leucine/genetics ; Mammals/genetics ; Repressor Proteins/metabolism ; Transcription Factors/chemistry ; Tripartite Motif-Containing Protein 28/chemistry ; Tripartite Motif-Containing Protein 28/genetics ; Tripartite Motif-Containing Protein 28/metabolism ; Zinc Fingers/genetics
Chemical Substances	Chromatin ; Co-Repressor Proteins ; Heterochromatin ; Repressor Proteins ; Transcription Factors ; Furylfuramide (054NR2135Y) ; Tripartite Motif-Containing Protein 28 (EC 2.3.2.27) ; Leucine (GMW67QNF9C)
Language	English
Publishing date	2022-09-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1106283-6
ISSN	1469-896X ; 0961-8368
ISSN (online)	1469-896X
ISSN	0961-8368
DOI	10.1002/pro.4436
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Article ; Online: Stress control for a well-structured life.

Goldstone, David C / Baker, Edward N

The Journal of biological chemistry

2018 Volume 293, Issue 16, Page(s) 5806–5807

Abstract: Aerobic life brings with it a need to respond to external redox stress in ways that preserve key processes. ...

Abstract	Aerobic life brings with it a need to respond to external redox stress in ways that preserve key processes.
MeSH term(s)	Bacteria/metabolism ; Bacterial Proteins/chemistry ; Bacterial Proteins/metabolism ; Copper/metabolism ; Disulfides/chemistry ; Disulfides/metabolism ; Escherichia coli/chemistry ; Escherichia coli/metabolism ; Escherichia coli Proteins/chemistry ; Escherichia coli Proteins/metabolism ; Models, Molecular ; Oxidation-Reduction ; Oxidoreductases/chemistry ; Oxidoreductases/metabolism ; Proteus mirabilis/chemistry ; Proteus mirabilis/metabolism ; Stress, Physiological
Chemical Substances	Bacterial Proteins ; Disulfides ; Escherichia coli Proteins ; Copper (789U1901C5) ; Oxidoreductases (EC 1.-) ; DsbD electron transport protein, E coli (EC 1.8.1.8)
Language	English
Publishing date	2018-04-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.H118.002699
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Article: AdductHunter: identifying protein-metal complex adducts in mass spectra.

Long, Derek / Eade, Liam / Sullivan, Matthew P / Dost, Katharina / Meier-Menches, Samuel M / Goldstone, David C / Hartinger, Christian G / Wicker, Jörg S / Taškova, Katerina

Journal of cheminformatics

2024 Volume 16, Issue 1, Page(s) 15

Abstract: Mass spectrometry (MS) is an analytical technique for molecule identification that can be used for investigating protein-metal complex interactions. Once the MS data is collected, the mass spectra are usually interpreted manually to identify the adducts ... ...

Abstract	Mass spectrometry (MS) is an analytical technique for molecule identification that can be used for investigating protein-metal complex interactions. Once the MS data is collected, the mass spectra are usually interpreted manually to identify the adducts formed as a result of the interactions between proteins and metal-based species. However, with increasing resolution, dataset size, and species complexity, the time required to identify adducts and the error-prone nature of manual assignment have become limiting factors in MS analysis. AdductHunter is a open-source web-based analysis tool that automates the peak identification process using constraint integer optimization to find feasible combinations of protein and fragments, and dynamic time warping to calculate the dissimilarity between the theoretical isotope pattern of a species and its experimental isotope peak distribution. Empirical evaluation on a collection of 22 unique MS datasetsshows fast and accurate identification of protein-metal complex adducts in deconvoluted mass spectra.
Language	English
Publishing date	2024-02-06
Publishing country	England
Document type	Journal Article
ZDB-ID	2486539-4
ISSN	1758-2946
ISSN	1758-2946
DOI	10.1186/s13321-023-00797-7
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Article ; Online: The RING domain of TRIM69 promotes higher-order assembly.

Keown, Jeremy R / Yang, Joy / Black, Moyra M / Goldstone, David C

Acta crystallographica. Section D, Structural biology

2020 Volume 76, Issue Pt 10, Page(s) 954–961

Abstract: Members of the TRIM protein family have been shown to inhibit a range of viral infections. Recently, TRIM69 was identified as a potent inhibitor of Vesicular stomatitis Indiana virus infection, with its inhibition being dependent upon multimerization. ... ...

Abstract	Members of the TRIM protein family have been shown to inhibit a range of viral infections. Recently, TRIM69 was identified as a potent inhibitor of Vesicular stomatitis Indiana virus infection, with its inhibition being dependent upon multimerization. Using SEC-MALLS analysis, it is demonstrated that the assembly of TRIM69 is mediated through the RING domain and not the Bbox domain as has been shown for other TRIM proteins. Using X-ray crystallography, the structure of the TRIM69 RING domain has been determined to a resolution of 2.1 Å, the oligomerization interface has been identified and regions outside the four-helix bundle have been observed to form interactions that are likely to support assembly.
Language	English
Publishing date	2020-09-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	2968623-4
ISSN	2059-7983 ; 0907-4449
ISSN (online)	2059-7983
ISSN	0907-4449
DOI	10.1107/S2059798320010499
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Article ; Online: Gel electrophoresis in combination with laser ablation-inductively coupled plasma mass spectrometry to quantify the interaction of cisplatin with human serum albumin.

Sullivan, Matthew P / Morrow, Stuart J / Goldstone, David C / Hartinger, Christian G

Electrophoresis

2019 Volume 40, Issue 18-19, Page(s) 2329–2335

Abstract: Cisplatin and its second and third generation analogues are widely used in the treatment of cancer. To study their reactions with proteins, we present a method based on SDS-PAGE separation and laser ablation-inductively coupled plasma-mass spectrometry ( ... ...

Abstract	Cisplatin and its second and third generation analogues are widely used in the treatment of cancer. To study their reactions with proteins, we present a method based on SDS-PAGE separation and laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) for platinum detection in the reaction between human serum albumin (HSA) and cisplatin. We developed matrix-matched standards of HSA/cisplatin mixtures and used them to quantify the amount of adducts formed at different HSA:cisplatin ratios. We noted that cisplatin incubation with HSA resulted in the formation of higher order HSA n-mers, depending on the amount of cisplatin added. This caused a depletion of the HSA dimer bands, while the majority of HSA was present as the monomer. Inducing the formation of such higher molecular weight species may have an impact on the mode of action of metallodrugs.
MeSH term(s)	Antineoplastic Agents/analysis ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/metabolism ; Cisplatin/analysis ; Cisplatin/chemistry ; Cisplatin/metabolism ; Humans ; Lasers ; Mass Spectrometry/methods ; Serum Albumin, Human/chemistry ; Serum Albumin, Human/metabolism
Chemical Substances	Antineoplastic Agents ; Cisplatin (Q20Q21Q62J) ; Serum Albumin, Human (ZIF514RVZR)
Language	English
Publishing date	2019-05-21
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	619001-7
ISSN	1522-2683 ; 0173-0835
ISSN (online)	1522-2683
ISSN	0173-0835
DOI	10.1002/elps.201900070
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ab Jg. 2022: Lesesaal (EG)

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Article ; Online: NlpC/P60 peptidoglycan hydrolases of Trichomonas vaginalis have complementary activities that empower the protozoan to control host-protective lactobacilli.

Barnett, Michael J / Pinheiro, Jully / Keown, Jeremy R / Biboy, Jacob / Gray, Joe / Lucinescu, Ioana-Wilhelmina / Vollmer, Waldemar / Hirt, Robert P / Simoes-Barbosa, Augusto / Goldstone, David C

PLoS pathogens

2023 Volume 19, Issue 8, Page(s) e1011563

Abstract: Trichomonas vaginalis is a human protozoan parasite that causes trichomoniasis, a prevalent sexually transmitted infection. Trichomoniasis is accompanied by a shift to a dysbiotic vaginal microbiome that is depleted of lactobacilli. Studies on co- ... ...

Abstract	Trichomonas vaginalis is a human protozoan parasite that causes trichomoniasis, a prevalent sexually transmitted infection. Trichomoniasis is accompanied by a shift to a dysbiotic vaginal microbiome that is depleted of lactobacilli. Studies on co-cultures have shown that vaginal bacteria in eubiosis (e.g. Lactobacillus gasseri) have antagonistic effects on T. vaginalis pathogenesis, suggesting that the parasite might benefit from shaping the microbiome to dysbiosis (e.g. Gardnerella vaginalis among other anaerobes). We have recently shown that T. vaginalis has acquired NlpC/P60 genes from bacteria, expanding them to a repertoire of nine TvNlpC genes in two distinct clans, and that TvNlpCs of clan A are active against bacterial peptidoglycan. Here, we expand this characterization to TvNlpCs of clan B. In this study, we show that the clan organisation of NlpC/P60 genes is a feature of other species of Trichomonas, and that Histomonas meleagridis has sequences related to one clan. We characterized the 3D structure of TvNlpC_B3 alone and with the inhibitor E64 bound, probing the active site of these enzymes for the first time. Lastly, we demonstrated that TvNlpC_B3 and TvNlpC_B5 have complementary activities with the previously described TvNlpCs of clan A and that exogenous expression of these enzymes empower this mucosal parasite to take over populations of vaginal lactobacilli in mixed cultures. TvNlpC_B3 helps control populations of L. gasseri, but not of G. vaginalis, which action is partially inhibited by E64. This study is one of the first to show how enzymes produced by a mucosal protozoan parasite may contribute to a shift on the status of a microbiome, helping explain the link between trichomoniasis and vaginal dysbiosis. Further understanding of this process might have significant implications for treatments in the future.
MeSH term(s)	Female ; Humans ; Trichomonas vaginalis/genetics ; Lactobacillus/genetics ; Peptidoglycan ; N-Acetylmuramoyl-L-alanine Amidase ; Dysbiosis ; Trichomonas Infections ; Bacteria ; Trichomonas Vaginitis
Chemical Substances	Peptidoglycan ; N-Acetylmuramoyl-L-alanine Amidase (EC 3.5.1.28)
Language	English
Publishing date	2023-08-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1011563
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Article ; Online: Platinum(terpyridine) complexes with N-heterocyclic carbene co-ligands: high antiproliferative activity and low toxicity

Sullivan, Matthew P / Adams, Muneebah / Riisom, Mie / Herbert, Caitlin D / Tong, Kelvin K H / Astin, Jonathan W / Jamieson, Stephen M F / Hanif, Muhammad / Goldstone, David C / Hartinger, Christian G

Dalton transactions (Cambridge, England : 2003)

2023 Volume 52, Issue 5, Page(s) 1388–1392

Abstract: Pt(terpyridine) complexes are well-known DNA intercalators. The introduction of an NHC co-ligand rendered such a complex highly antiproliferative in cancer cells compared to its chlorido derivative. Despite the high potency, zebrafish embryos tolerated ... ...

Abstract	Pt(terpyridine) complexes are well-known DNA intercalators. The introduction of an NHC co-ligand rendered such a complex highly antiproliferative in cancer cells compared to its chlorido derivative. Despite the high potency, zebrafish embryos tolerated the compound well, especially compared to cisplatin. DNA interaction studies support a mode of action related to intercalation.
MeSH term(s)	Animals ; Platinum ; Antineoplastic Agents/pharmacology ; Ligands ; Zebrafish ; Cell Line, Tumor ; DNA
Chemical Substances	Platinum (49DFR088MY) ; Antineoplastic Agents ; Ligands ; carbene (2465-56-7) ; DNA (9007-49-2)
Language	English
Publishing date	2023-01-31
Publishing country	England
Document type	Journal Article
ZDB-ID	1472887-4
ISSN	1477-9234 ; 1364-5447 ; 0300-9246 ; 1477-9226
ISSN (online)	1477-9234 ; 1364-5447
ISSN	0300-9246 ; 1477-9226
DOI	10.1039/d2dt02539f
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Article: Gel electrophoresis in combination with laser ablation–inductively coupled plasma mass spectrometry to quantify the interaction of cisplatin with human serum albumin

Sullivan, Matthew P / Goldstone, David C / Hartinger, Christian G / Morrow, Stuart J

Electrophoresis. 2019 Sept., v. 40, no. 18-19

2019

Abstract: Cisplatin and its second and third generation analogues are widely used in the treatment of cancer. To study their reactions with proteins, we present a method based on SDS‐PAGE separation and laser ablation–inductively coupled plasma‐mass spectrometry ( ... ...

Abstract	Cisplatin and its second and third generation analogues are widely used in the treatment of cancer. To study their reactions with proteins, we present a method based on SDS‐PAGE separation and laser ablation–inductively coupled plasma‐mass spectrometry (LA–ICP‐MS) for platinum detection in the reaction between human serum albumin (HSA) and cisplatin. We developed matrix‐matched standards of HSA/cisplatin mixtures and used them to quantify the amount of adducts formed at different HSA:cisplatin ratios. We noted that cisplatin incubation with HSA resulted in the formation of higher order HSA n‐mers, depending on the amount of cisplatin added. This caused a depletion of the HSA dimer bands, while the majority of HSA was present as the monomer. Inducing the formation of such higher molecular weight species may have an impact on the mode of action of metallodrugs.
Keywords	blood plasma ; cisplatin ; human serum albumin ; mass spectrometry ; mechanism of action ; molecular weight ; neoplasms ; platinum ; polyacrylamide gel electrophoresis
Language	English
Dates of publication	2019-09
Size	p. 2329-2335.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	JOURNAL ARTICLE
ZDB-ID	619001-7
ISSN	1522-2683 ; 0173-0835
ISSN (online)	1522-2683
ISSN	0173-0835
DOI	10.1002/elps.201900070
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Structural Analysis of the Menangle Virus P Protein Reveals a Soft Boundary between Ordered and Disordered Regions.

Webby, Melissa N / Herr, Nicole / Bulloch, Esther M M / Schmitz, Michael / Keown, Jeremy R / Goldstone, David C / Kingston, Richard L

Viruses

2021 Volume 13, Issue 9

Abstract: The paramyxoviral phosphoprotein (P protein) is the non-catalytic subunit of the viral RNA polymerase, and coordinates many of the molecular interactions required for RNA synthesis. All paramyxoviral P proteins oligomerize via a centrally located coiled- ... ...

Abstract	The paramyxoviral phosphoprotein (P protein) is the non-catalytic subunit of the viral RNA polymerase, and coordinates many of the molecular interactions required for RNA synthesis. All paramyxoviral P proteins oligomerize via a centrally located coiled-coil that is connected to a downstream binding domain by a dynamic linker. The C-terminal region of the P protein coordinates interactions between the catalytic subunit of the polymerase, and the viral nucleocapsid housing the genomic RNA. The inherent flexibility of the linker is believed to facilitate polymerase translocation. Here we report biophysical and structural characterization of the C-terminal region of the P protein from Menangle virus (MenV), a bat-borne paramyxovirus with zoonotic potential. The MenV P protein is tetrameric but can dissociate into dimers at sub-micromolar protein concentrations. The linker is globally disordered and can be modeled effectively as a worm-like chain. However, NMR analysis suggests very weak local preferences for alpha-helical and extended beta conformation exist within the linker. At the interface between the disordered linker and the structured C-terminal binding domain, a gradual disorder-to-order transition occurs, with X-ray crystallographic analysis revealing a dynamic interfacial structure that wraps the surface of the binding domain.
MeSH term(s)	Catalytic Domain ; Crystallography, X-Ray ; DNA-Directed RNA Polymerases ; Models, Molecular ; Paramyxoviridae/genetics ; Paramyxoviridae/metabolism ; Phosphoproteins/chemistry ; Phosphoproteins/genetics ; Protein Binding ; Protein Domains ; RNA, Viral ; Viral Proteins/chemistry ; Viral Proteins/genetics
Chemical Substances	Phosphoproteins ; RNA, Viral ; Viral Proteins ; DNA-Directed RNA Polymerases (EC 2.7.7.6)
Language	English
Publishing date	2021-08-31
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v13091737
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