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Article ; Online: SART3 associates with a post-splicing complex.

Klimešová, Klára / Petržílková, Hana / Bařinka, Cyril / Staněk, David

2023 Volume 136, Issue 2

Abstract: SART3 is a multifunctional protein that acts in several steps of gene expression, including assembly and recycling of the spliceosomal U4/U6 small nuclear ribonucleoprotein particle (snRNP). In this work, we provide evidence that SART3 associates via its ...

Abstract	SART3 is a multifunctional protein that acts in several steps of gene expression, including assembly and recycling of the spliceosomal U4/U6 small nuclear ribonucleoprotein particle (snRNP). In this work, we provide evidence that SART3 associates via its N-terminal HAT domain with the 12S U2 snRNP. Further analysis showed that SART3 associates with the post-splicing complex containing U2 and U5 snRNP components. In addition, we observed an interaction between SART3 and the RNA helicase DHX15, which disassembles post-splicing complexes. Based on our data, we propose a model that SART3 associates via its N-terminal HAT domain with the post-splicing complex, where it interacts with U6 snRNA to protect it and to initiate U6 snRNA recycling before a next round of splicing.
MeSH term(s)	RNA Splicing/genetics ; Spliceosomes/genetics ; Spliceosomes/metabolism ; RNA, Small Nuclear/genetics ; RNA, Small Nuclear/metabolism ; Ribonucleoprotein, U4-U6 Small Nuclear/genetics ; Ribonucleoprotein, U4-U6 Small Nuclear/metabolism ; Ribonucleoprotein, U5 Small Nuclear/genetics ; Ribonucleoprotein, U5 Small Nuclear/metabolism ; Ribonucleoprotein, U2 Small Nuclear/genetics ; Ribonucleoprotein, U2 Small Nuclear/metabolism ; Ribonucleoproteins, Small Nuclear/genetics ; Ribonucleoproteins, Small Nuclear/metabolism
Chemical Substances	RNA, Small Nuclear ; Ribonucleoprotein, U4-U6 Small Nuclear ; Ribonucleoprotein, U5 Small Nuclear ; Ribonucleoprotein, U2 Small Nuclear ; Ribonucleoproteins, Small Nuclear
Language	English
Publishing date	2023-01-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2993-2
ISSN	1477-9137 ; 0021-9533
ISSN (online)	1477-9137
ISSN	0021-9533
DOI	10.1242/jcs.260380
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Article ; Online: Comparative Structure-Based Virtual Screening Utilizing Optimized AlphaFold Model Identifies Selective HDAC11 Inhibitor.

Baselious, Fady / Hilscher, Sebastian / Robaa, Dina / Barinka, Cyril / Schutkowski, Mike / Sippl, Wolfgang

International journal of molecular sciences

2024 Volume 25, Issue 2

Abstract: HDAC11 is a class IV histone deacylase with no crystal structure reported so far. The catalytic domain of HDAC11 shares low sequence identity with other HDAC isoforms, which makes conventional homology modeling less reliable. AlphaFold is a machine ... ...

Abstract	HDAC11 is a class IV histone deacylase with no crystal structure reported so far. The catalytic domain of HDAC11 shares low sequence identity with other HDAC isoforms, which makes conventional homology modeling less reliable. AlphaFold is a machine learning approach that can predict the 3D structure of proteins with high accuracy even in absence of similar structures. However, the fact that AlphaFold models are predicted in the absence of small molecules and ions/cofactors complicates their utilization for drug design. Previously, we optimized an HDAC11 AlphaFold model by adding the catalytic zinc ion and minimization in the presence of reported HDAC11 inhibitors. In the current study, we implement a comparative structure-based virtual screening approach utilizing the previously optimized HDAC11 AlphaFold model to identify novel and selective HDAC11 inhibitors. The stepwise virtual screening approach was successful in identifying a hit that was subsequently tested using an in vitro enzymatic assay. The hit compound showed an IC
MeSH term(s)	Molecular Docking Simulation ; Molecular Dynamics Simulation ; Catalytic Domain ; Models, Chemical ; Drug Design ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylase Inhibitors/chemistry
Chemical Substances	Histone Deacetylase Inhibitors
Language	English
Publishing date	2024-01-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms25021358
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Article ; Online: Tunable Multivalent Platform for Immune Recruitment to Lower Antigen Expressing Cancers.

Lake, Benjamin P M / Wylie, Ryan G / Bařinka, Cyril / Rullo, Anthony F

Angewandte Chemie (International ed. in English)

2023 Volume 62, Issue 9, Page(s) e202214659

Abstract: Chemical immunotherapeutic strategies including Antibody Recruiting Molecules (ARMs - bivalent small molecules containing an antibody-binding domain (ABD) and a target-binding domain (TBD)) direct immune-mediated clearance of diseased cells. Anti-cancer ... ...

Abstract	Chemical immunotherapeutic strategies including Antibody Recruiting Molecules (ARMs - bivalent small molecules containing an antibody-binding domain (ABD) and a target-binding domain (TBD)) direct immune-mediated clearance of diseased cells. Anti-cancer ARM function relies on high tumor antigen valency, limiting function against lower antigen expressing tumors. To address this limitation, we report a tunable multivalent immune recruitment (MIR) platform to amplify/stabilize antibody recruitment to cells with lower antigen valencies. An initial set of polymeric ARMs (pARMs) were synthesized and screened to evaluate ABD/TBD copy number, ratio, and steric occlusion on specific immune induction. Most pARMs demonstrated simultaneous high avidity binding to anti-dinitrophenyl antibodies and prostate-specific membrane antigens on prostate cancer. Optimized pARMs mediated enhanced anti-cancer immune function against lower antigen expressing target cells compared to an analogous ARM.
MeSH term(s)	Male ; Humans ; Antigens ; Antibodies/chemistry ; Prostatic Neoplasms ; Phagocytosis
Chemical Substances	Antigens ; Antibodies
Language	English
Publishing date	2023-01-23
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2011836-3
ISSN	1521-3773 ; 1433-7851
ISSN (online)	1521-3773
ISSN	1433-7851
DOI	10.1002/anie.202214659
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Article: Galectin-3-binding protein inhibits extracellular heparan 6-

Panigrahi, Aswini / Benicky, Julius / Aljuhani, Reem / Mukherjee, Pritha / Nováková, Zora / Bařinka, Cyril / Goldman, Radoslav

bioRxiv : the preprint server for biology

2023

Abstract: Human extracellular 6- ...

Abstract	Human extracellular 6-
Language	English
Publishing date	2023-12-21
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.12.20.572603
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Article ; Online: Targeting Prostate Cancer Using Bispecific T-Cell Engagers against Prostate-Specific Membrane Antigen.

Das, Gargi / Ptacek, Jakub / Havlinova, Barbora / Nedvedova, Jana / Barinka, Cyril / Novakova, Zora

ACS pharmacology & translational science

2023 Volume 6, Issue 11, Page(s) 1703–1714

Abstract: Prostate cancer (PCa) tops the list of cancer-related deaths in men worldwide. Prostate-specific membrane antigen (PSMA) is currently the most prominent PCa biomarker, as its expression levels are robustly enhanced in advanced stages of PCa. As such, ... ...

Abstract	Prostate cancer (PCa) tops the list of cancer-related deaths in men worldwide. Prostate-specific membrane antigen (PSMA) is currently the most prominent PCa biomarker, as its expression levels are robustly enhanced in advanced stages of PCa. As such, PSMA targeting is highly efficient in PCa imaging as well as therapy. For the latter, PSMA-positive tumors can be targeted directly by using small molecules or macromolecules with cytotoxic payloads or indirectly by engaging the immune system of the host. Here we describe the engineering, expression, purification, and biological characterization of bispecific T-cell engagers (BiTEs) that enable targeting PSMA-positive tumor cells by host T lymphocytes. To this end, we designed the 5D3-αCD3 BiTE as a fusion of single-chain fragments of PSMA-specific 5D3 and anti-CD3 antibodies. Detailed characterization of BiTE was performed by a combination of size-exclusion chromatography, differential scanning fluorimetry, and flow cytometry. Expressed in insect cells, BiTE was purified in monodisperse form and retained thermal stability of both functional parts and nanomolar affinity to respective antigens. 5D3-αCD3's efficiency and specificity were further evaluated
Language	English
Publishing date	2023-10-06
Publishing country	United States
Document type	Journal Article
ISSN	2575-9108
ISSN (online)	2575-9108
DOI	10.1021/acsptsci.3c00159
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Article: Development and therapeutic evaluation of 5D3(CC-MLN8237)

Liatsou, Ioanna / Assefa, Betelhem / Liyanage, Wathsala / Surasinghe, Sharmane / Nováková, Zora / Bařinka, Cyril / Gabrielson, Kathleen / Raman, Venu / Artemov, Dmitri / Hapuarachchige, Sudath

Frontiers in pharmacology

2024 Volume 15, Page(s) 1385598

Abstract: Prostate cancer (PC) is an aggressive cancer that can progress rapidly and eventually become castrate-resistant prostate cancer (CRPC). Stage IV metastatic castrate-resistant prostate cancer (mCRPC) is an incurable late-stage cancer type with a low 5- ... ...

Abstract	Prostate cancer (PC) is an aggressive cancer that can progress rapidly and eventually become castrate-resistant prostate cancer (CRPC). Stage IV metastatic castrate-resistant prostate cancer (mCRPC) is an incurable late-stage cancer type with a low 5-year overall survival rate. Targeted therapeutics such as antibody-drug conjugates (ADCs) based on high-affinity monoclonal antibodies and potent drugs conjugated via smart linkers are being developed for PC management. Conjugating further with
Language	English
Publishing date	2024-05-01
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2024.1385598
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Article: Molecular characterization of a novel His333Arg variant of human protoporphyrinogen oxidase IX

Novakova, Zora / Mikesova, Jana / Ondrakova, Marketa / Kutil, Zsofia / Vesela, Katerina / Martasek, Pavel / Barinka, Cyril

Biochemical and biophysical research communications. 2022 Jan. 15, v. 588

2022

Abstract: Variegate porphyria is caused by mutations in the protoporphyrinogen oxidase IX (PPOX, EC 1.3.3.4) gene, resulting in reduced overall enzymatic activity of PPOX in human tissues. Recently, we have identified the His333Arg mutation in the PPOX protein ( ... ...

Abstract	Variegate porphyria is caused by mutations in the protoporphyrinogen oxidase IX (PPOX, EC 1.3.3.4) gene, resulting in reduced overall enzymatic activity of PPOX in human tissues. Recently, we have identified the His333Arg mutation in the PPOX protein (PPOX(H333R)) as a putative founder mutation in the Moroccan Jewish population. Herein we report the molecular characterization of PPOX(H333R) in vitro and in cells. Purified recombinant PPOX(H333R) did not show any appreciable enzymatic activity in vitro, corroborating the clinical findings. Biophysical experiments and molecular modeling revealed that PPOX(H333R) is not folded properly and fails to adopt its native functional three-dimensional conformation due to steric clashes in the vicinity of the active site of the enzyme. On the other hand, PPOX(H333R) subcellular distribution, as evaluated by live-cell confocal microscopy, is unimpaired suggesting that the functional three-dimensional fold is not required for efficient transport of the polypeptide chain into mitochondria. Overall, the data presented here provide molecular underpinnings of the pathogenicity of PPOX(H333R) and might serve as a blueprint for deciphering whether a given PPOX variant represents a disease-causing mutation.
Keywords	Jews ; active sites ; confocal microscopy ; enzyme activity ; genes ; humans ; mitochondria ; mutation ; pathogenicity ; polypeptides ; porphyria ; protoporphyrinogen oxidase ; research
Language	English
Dates of publication	2022-0115
Size	p. 182-186.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	205723-2
ISSN	0006-291X ; 0006-291X
ISSN (online)	0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2021.12.062
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Article ; Online: Uncovering Robust Delactoylase and Depyruvoylase Activities of HDAC Isoforms.

Zessin, Matthes / Meleshin, Marat / Praetorius, Lucas / Sippl, Wolfgang / Bařinka, Cyril / Schutkowski, Mike

ACS chemical biology

2022 Volume 17, Issue 6, Page(s) 1364–1375

Abstract: Zinc-dependent histone deacetylases (HDACs) and sirtuins (SIRT) represent two different classes of enzymes which are responsible for deacylation of modified lysine side chains. The repertoire of acyl residues on lysine side chains ... ...

Abstract	Zinc-dependent histone deacetylases (HDACs) and sirtuins (SIRT) represent two different classes of enzymes which are responsible for deacylation of modified lysine side chains. The repertoire of acyl residues on lysine side chains identified
MeSH term(s)	Aging ; Histone Deacetylase Inhibitors ; Histone Deacetylases ; Humans ; Lysine/chemistry ; Protein Isoforms ; Repressor Proteins/metabolism ; Sirtuin 2 ; Zinc
Chemical Substances	Histone Deacetylase Inhibitors ; Protein Isoforms ; Repressor Proteins ; Sirtuin 2 (EC 3.5.1.-) ; HDAC8 protein, human (EC 3.5.1.98) ; Histone Deacetylases (EC 3.5.1.98) ; Zinc (J41CSQ7QDS) ; Lysine (K3Z4F929H6)
Language	English
Publishing date	2022-05-31
Publishing country	United States
Document type	Journal Article ; Systematic Review ; Research Support, Non-U.S. Gov't
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/acschembio.1c00863
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Article ; Online: Characterization of the class IIa histone deacetylases substrate specificity.

Kutil, Zsofia / Meleshin, Marat / Baranova, Petra / Havlinova, Barbora / Schutkowski, Mike / Barinka, Cyril

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2022 Volume 36, Issue 5, Page(s) e22287

Abstract: Class IIa histone deacetylases (HDACs) play critical roles in vertebrate development and physiology, yet direct evidence of their intrinsic deacetylase activity and on substrate specificity regarding the peptide sequence is still missing. In this study, ... ...

Abstract	Class IIa histone deacetylases (HDACs) play critical roles in vertebrate development and physiology, yet direct evidence of their intrinsic deacetylase activity and on substrate specificity regarding the peptide sequence is still missing. In this study, we designed and synthesized a combinatorial peptide library allowing us to profile class IIa HDACs sequence specificity at positions +3 through -3 from the central lysine modified by the well-accepted trifluoroacetyl function. Our data revealed a strong preference for bulky aromatic acids directly flanking the central trifluoroacetyllysine, while all class IIa HDACs disfavor positively charged residues and proline at the +1/-1 positions. The chemical nature of amino acid residues N-terminally to the central trifluoroacetyllysine has a more profound effect on substrate recognition as compared to residues located C-terminally. These findings were validated by designing selected favored and disfavored peptide sequences, with the favored ones are accepted with catalytic efficacy of 75 000 and 525 000 M
MeSH term(s)	Amino Acid Sequence ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylases/genetics ; Histone Deacetylases/metabolism ; Peptides ; Substrate Specificity
Chemical Substances	Histone Deacetylase Inhibitors ; Peptides ; Histone Deacetylases (EC 3.5.1.98)
Language	English
Publishing date	2022-03-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.202101663R
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Article ; Online: Determining Potency of Inhibitors Targeting Histone Deacetylase 6 by Quantification of Acetylated Tubulin in Cells.

Mikesova, Jana / Ondrakova, Marketa / Jelinkova, Iva / Ptacek, Jakub / Novakova, Zora / Barinka, Cyril

Methods in molecular biology (Clifton, N.J.)

2022 Volume 2589, Page(s) 455–466

Abstract: During the preclinical development of small molecule inhibitors, compounds or compound libraries are typically first screened using purified target enzymes in vitro to select candidates with high potency. In the later stages of the development, however, ... ...

Abstract	During the preclinical development of small molecule inhibitors, compounds or compound libraries are typically first screened using purified target enzymes in vitro to select candidates with high potency. In the later stages of the development, however, functional cell-based assays may provide biologically more relevant data. In this chapter, we describe a detailed protocol for determining the potency of inhibitors targeting human histone deacetylase 6 in complex cellular environments. Cells are first treated with a dilution series of tested compounds, cell lysates separated by SDS-PAGE, and electrotransferred to a blotting membrane. The inhibitor potency is then determined indirectly by quantifying the levels of acetylated tubulin as a surrogate readout.
MeSH term(s)	Humans ; Histone Deacetylase 6/metabolism ; Tubulin/metabolism ; Histone Deacetylase Inhibitors/pharmacology ; Acetylation
Chemical Substances	Histone Deacetylase 6 (EC 3.5.1.98) ; Tubulin ; Histone Deacetylase Inhibitors
Language	English
Publishing date	2022-10-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-2788-4_29
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