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Article: Structural Basis of Parasitic HSP90 ATPase Inhibition by Small Molecules.

Tassone, Giusy / Mazzorana, Marco / Pozzi, Cecilia

2022 Volume 15, Issue 11

Abstract: Protozoan parasites are responsible for several harmful and widespread human diseases that cause high morbidity and mortality. Currently available treatments have serious limitations due to poor efficiency, strong adverse effects, and high cost. Hence, ... ...

Abstract	Protozoan parasites are responsible for several harmful and widespread human diseases that cause high morbidity and mortality. Currently available treatments have serious limitations due to poor efficiency, strong adverse effects, and high cost. Hence, the identification of new targets and the development of specific drug therapies against parasitic diseases are urgent needs. Heat shock protein 90 (HSP90) is an ATP-dependent molecular chaperone that plays a key role in parasite survival during the various differentiation stages, spread over the vector insect and the human host, which they undergo during their life cycle. The N-terminal domain (NTD) of HSP90, containing the main determinants for ATPase activity, represents the most druggable domain for inhibitor targeting. The molecules investigated on parasite HSP90 are mainly developed from known inhibitors of the human counterpart, and they have strong limitations due to selectivity issues, accounting for the high conservation of the ATP-binding site between the parasite and human proteins. The current review highlights the recent structural progress made to support the rational design of new molecules able to effectively block the chaperone activity of parasite HSP90.
Language	English
Publishing date	2022-10-29
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph15111341
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Article ; Online: Calcium-Induced Protein Folding in Calumenin and Calmodulin.

Mazzorana, Marco / Sørensen, Thomas Lykke-Møller

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

2019 Volume 1929, Page(s) 517–537

Abstract: ... trilobal fold in the presence of calcium (Mazzorana et al., PLoS One 11:e0151547, 2016).Here, we describe ...

Abstract	Binding of calcium - and small molecules in general - often induce conformational changes in large molecules and complexes. The degree and type of change varies, but the resulting shift in specific affinities ultimately induces a physiological response. It is therefore important for our understanding of responses at the cellular level to define coupled changes at the molecular level.Calumenin, a six-EF-hand calcium-binding protein localized in the endoplasmic reticulum, undergoes substantial calcium-induced rearrangement. We have demonstrated how calumenin changes from being unfolded in the absence of calcium to a compact trilobal fold in the presence of calcium (Mazzorana et al., PLoS One 11:e0151547, 2016).Here, we describe protocols for the expression and purification of calumenin and calmodulin, another EF-hand protein modulated by calcium, along with protocols for biophysical techniques used to characterize calcium-induced changes to protein conformation. Analytical size-exclusion chromatography in the presence and absence of calcium provides an informed indication of any larger conformational movements. Circular dichroism spectroscopy reveals alterations to the secondary or tertiary structure, while small-angle X-ray scattering explores changes further providing low-resolution conformational details.Surface plasmon resonance estimates binding kinetics and affinities completing the biophysical description of these events.
MeSH term(s)	Calcium/metabolism ; Calcium Signaling ; Calcium-Binding Proteins/chemistry ; Calcium-Binding Proteins/metabolism ; Calmodulin/chemistry ; Calmodulin/metabolism ; Circular Dichroism ; Endoplasmic Reticulum/metabolism ; Kinetics ; Magnetic Resonance Spectroscopy ; Models, Molecular ; Protein Binding ; Protein Conformation ; Protein Folding ; Scattering, Small Angle ; X-Ray Diffraction
Chemical Substances	CALU protein, human ; Calcium-Binding Proteins ; Calmodulin ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2019-02-01
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-9030-6_32
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Article ; Online: Structural Basis of Parasitic HSP90 ATPase Inhibition by Small Molecules

Giusy Tassone / Marco Mazzorana / Cecilia Pozzi

Pharmaceuticals, Vol 15, Iss 1341, p

2022 Volume 1341

Abstract	Protozoan parasites are responsible for several harmful and widespread human diseases that cause high morbidity and mortality. Currently available treatments have serious limitations due to poor efficiency, strong adverse effects, and high cost. Hence, the identification of new targets and the development of specific drug therapies against parasitic diseases are urgent needs. Heat shock protein 90 (HSP90) is an ATP-dependent molecular chaperone that plays a key role in parasite survival during the various differentiation stages, spread over the vector insect and the human host, which they undergo during their life cycle. The N-terminal domain (NTD) of HSP90, containing the main determinants for ATPase activity, represents the most druggable domain for inhibitor targeting. The molecules investigated on parasite HSP90 are mainly developed from known inhibitors of the human counterpart, and they have strong limitations due to selectivity issues, accounting for the high conservation of the ATP-binding site between the parasite and human proteins. The current review highlights the recent structural progress made to support the rational design of new molecules able to effectively block the chaperone activity of parasite HSP90.
Keywords	heat shock proteins ; HSP90 ; protozoan parasites ; neglected tropical diseases ; inhibitors ; selectivity ; Medicine ; R ; Pharmacy and materia medica ; RS1-441
Subject code	572
Language	English
Publishing date	2022-10-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: A comprehensive approach to X-ray crystallography for drug discovery at a synchrotron facility - The example of Diamond Light Source.

Mazzorana, Marco / Shotton, Elizabeth J / Hall, David R

Drug discovery today. Technologies

2020 Volume 37, Page(s) 83–92

Abstract: A detailed understanding of the interactions between drugs and their targets is crucial to develop the best possible therapeutic agents. Structure-based drug design relies on the availability of high-resolution structures obtained primarily through X-ray ...

Abstract	A detailed understanding of the interactions between drugs and their targets is crucial to develop the best possible therapeutic agents. Structure-based drug design relies on the availability of high-resolution structures obtained primarily through X-ray crystallography. Collecting and analysing quickly a large quantity of structural data is crucial to accelerate drug discovery pipelines. Researchers from academia and industry can access the highly automated macromolecular crystallography (MX) beamlines of Diamond Light Source, the UK national synchrotron, to rapidly collect diffraction data from large numbers of crystals. With seven beamlines dedicated to MX, Diamond offers bespoke solutions for a wide variety of user requirements. Working in synergy with state-of-the-art laboratories and other life science instruments to provide an integrated offering, the MX beamlines provide innovative and multidisciplinary approaches to the determination of structures of new pharmacological targets as well as the efficient study of protein-ligand complexes.
MeSH term(s)	Crystallography, X-Ray ; Drug Discovery ; Macromolecular Substances ; Synchrotrons
Chemical Substances	Macromolecular Substances
Language	English
Publishing date	2020-12-10
Publishing country	England
Document type	Journal Article ; Review
ISSN	1740-6749
ISSN (online)	1740-6749
DOI	10.1016/j.ddtec.2020.10.003
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Article ; Online: Structural Characterization of Human Heat Shock Protein 90 N-Terminal Domain and Its Variants K112R and K112A in Complex with a Potent 1,2,3-Triazole-Based Inhibitor.

Tassone, Giusy / Mazzorana, Marco / Mangani, Stefano / Petricci, Elena / Cini, Elena / Giannini, Giuseppe / Pozzi, Cecilia / Maramai, Samuele

International journal of molecular sciences

2022 Volume 23, Issue 16

Abstract: Heat shock protein 90 (Hsp90) is a ubiquitous molecular chaperone that stabilizes client proteins in a folded and functional state. It is composed of two identical and symmetrical subunits and each monomer consists of three domains, the N-terminal (NTD), ...

Abstract	Heat shock protein 90 (Hsp90) is a ubiquitous molecular chaperone that stabilizes client proteins in a folded and functional state. It is composed of two identical and symmetrical subunits and each monomer consists of three domains, the N-terminal (NTD), the middle (MD), and the C-terminal domain (CTD). Since the chaperone activity requires ATP hydrolysis, molecules able to occupy the ATP-binding pocket in the NTD act as Hsp90 inhibitors, leading to client protein degradation and cell death. Therefore, human Hsp90 represents a validated target for developing new anticancer drugs. Since protozoan parasites use their Hsp90 to trigger important transitions between different stages of their life cycle, this protein also represents a profitable target in anti-parasite drug discovery. Nevertheless, the development of molecules able to selectively target the ATP-binding site of protozoan Hsp90 is challenging due to the high homology with the human Hsp90 NTD (hHsp90-NTD). In a previous work, a series of potent Hsp90 inhibitors based on a 1,4,5-trisubstituted 1,2,3-triazole scaffold was developed. The most promising inhibitor of the series, JMC31, showed potent Hsp90 binding and antiproliferative activity in NCI-H460 cells in the low-nanomolar range. In this work, we present the structural characterization of hHsp90-NTD in complex with JMC31 through X-ray crystallography. In addition, to elucidate the role of residue 112 on the ligand binding and its exploitability for the development of selective inhibitors, we investigated the crystal structures of hHsp90-NTD variants (K112R and K112A) in complex with JMC31.
MeSH term(s)	Adenosine Triphosphate/metabolism ; Binding Sites ; HSP90 Heat-Shock Proteins/metabolism ; Humans ; Molecular Chaperones/metabolism ; Protein Binding ; Triazoles/pharmacology
Chemical Substances	HSP90 Heat-Shock Proteins ; Molecular Chaperones ; Triazoles ; Adenosine Triphosphate (8L70Q75FXE)
Language	English
Publishing date	2022-08-21
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/ijms23169458
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Article ; Online: Antitarget, Anti-SARS-CoV-2 Leads, Drugs, and the Drug Discovery-Genetics Alliance Perspective.

Pozzi, Cecilia / Vanet, Anne / Francesconi, Valeria / Tagliazucchi, Lorenzo / Tassone, Giusy / Venturelli, Alberto / Spyrakis, Francesca / Mazzorana, Marco / Costi, Maria P / Tonelli, Michele

Journal of medicinal chemistry

2023 Volume 66, Issue 6, Page(s) 3664–3702

Abstract: The most advanced antiviral molecules addressing major SARS-CoV-2 targets (Main protease, Spike protein, and RNA polymerase), compared with proteins of other human pathogenic coronaviruses, may have a short-lasting clinical efficacy. Accumulating ... ...

Abstract	The most advanced antiviral molecules addressing major SARS-CoV-2 targets (Main protease, Spike protein, and RNA polymerase), compared with proteins of other human pathogenic coronaviruses, may have a short-lasting clinical efficacy. Accumulating knowledge on the mechanisms underlying the target structural basis, its mutational progression, and the related biological significance to virus replication allows envisaging the development of better-targeted therapies in the context of COVID-19 epidemic and future coronavirus outbreaks. The identification of evolutionary patterns based solely on sequence information analysis for those targets can provide meaningful insights into the molecular basis of host-pathogen interactions and adaptation, leading to drug resistance phenomena. Herein, we will explore how the study of observed and predicted mutations may offer valuable suggestions for the application of the so-called "synthetic lethal" strategy to SARS-CoV-2 Main protease and Spike protein. The synergy between genetics evidence and drug discovery may prioritize the development of novel long-lasting antiviral agents.
MeSH term(s)	Humans ; SARS-CoV-2/metabolism ; COVID-19/epidemiology ; Spike Glycoprotein, Coronavirus ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Antiviral Agents/chemistry ; Drug Discovery
Chemical Substances	Spike Glycoprotein, Coronavirus ; Antiviral Agents ; spike protein, SARS-CoV-2
Language	English
Publishing date	2023-03-01
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.2c01229
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Article ; Online: Structural Characterization of Human Heat Shock Protein 90 N-Terminal Domain and Its Variants K112R and K112A in Complex with a Potent 1,2,3-Triazole-Based Inhibitor

Giusy Tassone / Marco Mazzorana / Stefano Mangani / Elena Petricci / Elena Cini / Giuseppe Giannini / Cecilia Pozzi / Samuele Maramai

International Journal of Molecular Sciences, Vol 23, Iss 16, p

2022 Volume 9458

Abstract	Heat shock protein 90 (Hsp90) is a ubiquitous molecular chaperone that stabilizes client proteins in a folded and functional state. It is composed of two identical and symmetrical subunits and each monomer consists of three domains, the N-terminal (NTD), the middle (MD), and the C-terminal domain (CTD). Since the chaperone activity requires ATP hydrolysis, molecules able to occupy the ATP-binding pocket in the NTD act as Hsp90 inhibitors, leading to client protein degradation and cell death. Therefore, human Hsp90 represents a validated target for developing new anticancer drugs. Since protozoan parasites use their Hsp90 to trigger important transitions between different stages of their life cycle, this protein also represents a profitable target in anti-parasite drug discovery. Nevertheless, the development of molecules able to selectively target the ATP-binding site of protozoan Hsp90 is challenging due to the high homology with the human Hsp90 NTD (hHsp90-NTD). In a previous work, a series of potent Hsp90 inhibitors based on a 1,4,5-trisubstituted 1,2,3-triazole scaffold was developed. The most promising inhibitor of the series, JMC31, showed potent Hsp90 binding and antiproliferative activity in NCI-H460 cells in the low-nanomolar range. In this work, we present the structural characterization of hHsp90-NTD in complex with JMC31 through X-ray crystallography. In addition, to elucidate the role of residue 112 on the ligand binding and its exploitability for the development of selective inhibitors, we investigated the crystal structures of hHsp90-NTD variants (K112R and K112A) in complex with JMC31.
Keywords	Hsp90 ; X-ray crystallography ; protein-inhibitor complex ; 1,2,3-triazole-based inhibitor ; selectivity ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Language	English
Publishing date	2022-08-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Ca-Dependent Folding of Human Calumenin.

Mazzorana, Marco / Hussain, Rohanah / Sorensen, Thomas

PloS one

2016 Volume 11, Issue 3, Page(s) e0151547

Abstract: Human calumenin (hCALU) is a six EF-hand protein belonging to the CREC family. As other members of the family, it is localized in the secretory pathway and regulates the activity of SERCA2a and of the ryanodine receptor in the endoplasmic reticulum (ER). ...

Abstract	Human calumenin (hCALU) is a six EF-hand protein belonging to the CREC family. As other members of the family, it is localized in the secretory pathway and regulates the activity of SERCA2a and of the ryanodine receptor in the endoplasmic reticulum (ER). We have studied the effects of Ca2+ binding to the protein and found it to attain a more compact structure upon ion binding. Circular Dichroism (CD) measurements suggest a major rearrangement of the protein secondary structure, which reversibly switches from disordered at low Ca2+ concentrations to predominantly alpha-helical when Ca2+ is added. SAXS experiments confirm the transition from an unfolded to a compact structure, which matches the structural prediction of a trilobal fold. Overall our experiments suggest that calumenin is a Ca2+ sensor, which folds into a compact structure, capable of interacting with its molecular partners, when Ca2+ concentration within the ER reaches the millimolar range.
MeSH term(s)	Amino Acid Sequence ; Calcium/chemistry ; Calcium-Binding Proteins/metabolism ; Circular Dichroism ; Cloning, Molecular ; Escherichia coli/genetics ; Escherichia coli/metabolism ; Humans ; Protein Binding ; Protein Folding/drug effects ; Protein Structure, Tertiary/physiology ; Scattering, Small Angle ; Surface Plasmon Resonance ; X-Ray Diffraction
Chemical Substances	CALU protein, human ; Calcium-Binding Proteins ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2016-03-18
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0151547
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Article ; Online: Ca-Dependent Folding of Human Calumenin.

Marco Mazzorana / Rohanah Hussain / Thomas Sorensen

PLoS ONE, Vol 11, Iss 3, p e

2016 Volume 0151547

Abstract	Human calumenin (hCALU) is a six EF-hand protein belonging to the CREC family. As other members of the family, it is localized in the secretory pathway and regulates the activity of SERCA2a and of the ryanodine receptor in the endoplasmic reticulum (ER). We have studied the effects of Ca2+ binding to the protein and found it to attain a more compact structure upon ion binding. Circular Dichroism (CD) measurements suggest a major rearrangement of the protein secondary structure, which reversibly switches from disordered at low Ca2+ concentrations to predominantly alpha-helical when Ca2+ is added. SAXS experiments confirm the transition from an unfolded to a compact structure, which matches the structural prediction of a trilobal fold. Overall our experiments suggest that calumenin is a Ca2+ sensor, which folds into a compact structure, capable of interacting with its molecular partners, when Ca2+ concentration within the ER reaches the millimolar range.
Keywords	Medicine ; R ; Science ; Q
Subject code	612
Language	English
Publishing date	2016-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: Fam20C-mediated phosphorylation of osteopontin is critical for its secretion but dispensable for its action as a cytokine in the activation of hepatic stellate cells in liver fibrogenesis.

Tibaldi, Elena / Brocca, Alessandra / Sticca, Antonietta / Gola, Elisabetta / Pizzi, Marco / Bordin, Luciana / Pagano, Mario Angelo / Mazzorana, Marco / Donà, Gabriella / Violi, Paola / Marin, Oriano / Romano, Antonella / Angeli, Paolo / Carraro, Amedeo / Brunati, Anna Maria

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

2019 Volume 34, Issue 1, Page(s) 1122–1135

Abstract: Osteopontin (OPN) is a phosphoglycoprotein secreted into the extracellular matrix upon liver injury, acting as a cytokine stimulates the deposition of fibrillary collagen in liver fibrogenesis. In livers of mice subjected to bile duct ligation (BDL) and ... ...

Abstract	Osteopontin (OPN) is a phosphoglycoprotein secreted into the extracellular matrix upon liver injury, acting as a cytokine stimulates the deposition of fibrillary collagen in liver fibrogenesis. In livers of mice subjected to bile duct ligation (BDL) and in cultured activated hepatic stellate cells (HSCs), we show that OPN, besides being overexpressed, is substantially phosphorylated by family with sequence similarity 20, member C (Fam20C), formerly known as Golgi casein kinase (G-CK), which is exclusively resident in the Golgi apparatus. In both experimental models, Fam20C becomes overactive when associated with a 500-kDa multiprotein complex, as compared with the negligible activity in livers of sham-operated rats and in quiescent HSCs. Fam20C knockdown not only confirmed the role of Fam20C itself in OPN phosphorylation, but also revealed that phosphorylation was essential for OPN secretion. However, OPN acts as a fibrogenic factor independently of its phosphorylation state, as demonstrated by the increased expression of Collagen-I by HSCs incubated with either a phosphorylated or nonphosphorylated form of recombinant OPN. Collectively, our results confirm that OPN promotes liver fibrosis and highlight Fam20C as a novel factor driving this process by favoring OPN secretion from HSCs, opening new avenues for deciphering yet unidentified mechanisms underlying liver fibrogenesis.
MeSH term(s)	Animals ; Calcium-Binding Proteins/metabolism ; Cytokines/metabolism ; Extracellular Matrix Proteins/metabolism ; Hepatic Stellate Cells/metabolism ; Liver/metabolism ; Liver/pathology ; Liver Cirrhosis/metabolism ; Male ; Mice ; Mice, Knockout ; Osteopontin/metabolism ; Phosphorylation ; Protein-Serine-Threonine Kinases/metabolism ; Rats ; Rats, Wistar ; Signal Transduction
Chemical Substances	Calcium-Binding Proteins ; Cytokines ; Extracellular Matrix Proteins ; FAM20C protein, mouse ; Spp1 protein, mouse ; Spp1 protein, rat ; Osteopontin (106441-73-0) ; Fam20C protein, rat (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2019-11-29
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.201900880R
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