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Article ; Online: Discovery and Characterization of a Cryptic Secondary Binding Site in the Molecular Chaperone HSP70

Suzanne O’Connor / Yann-Vaï Le Bihan / Isaac M. Westwood / Manjuan Liu / Oi Wei Mak / Gabriel Zazeri / Ana P. R. Povinelli / Alan M. Jones / Rob van Montfort / Jóhannes Reynisson / Ian Collins

Molecules, Vol 27, Iss 817, p

2022 Volume 817

Abstract: Heat Shock Protein 70s (HSP70s) are key molecular chaperones that are overexpressed in many cancers and often associated with metastasis and poor prognosis. It has proven difficult to develop ATP-competitive, drug-like small molecule inhibitors of HSP70s ...

Abstract	Heat Shock Protein 70s (HSP70s) are key molecular chaperones that are overexpressed in many cancers and often associated with metastasis and poor prognosis. It has proven difficult to develop ATP-competitive, drug-like small molecule inhibitors of HSP70s due to the flexible and hydrophilic nature of the HSP70 ATP-binding site and its high affinity for endogenous nucleotides. The aim of this study was to explore the potential for the inhibition of HSP70 through alternative binding sites using fragment-based approaches. A surface plasmon resonance (SPR) fragment screen designed to detect secondary binding sites in HSP70 led to the identification by X-ray crystallography of a cryptic binding site in the nucleotide-binding domain (NBD) of HSP70 adjacent to the ATP-binding site. Fragment binding was confirmed and characterized as ATP-competitive using SPR and ligand-observed NMR methods. Molecular dynamics simulations were applied to understand the interactions with the protein upon ligand binding, and local secondary structure changes consistent with interconversion between the observed crystal structures with and without the cryptic pocket were detected. A virtual high-throughput screen (vHTS) against the cryptic pocket was conducted, and five compounds with diverse chemical scaffolds were confirmed to bind to HSP70 with micromolar affinity by SPR. These results identified and characterized a new targetable site on HSP70. While targeting HSP70 remains challenging, the new site may provide opportunities to develop allosteric ATP-competitive inhibitors with differentiated physicochemical properties from current series.
Keywords	HSP70 ; cryptic pocket ; fragment screen ; virtual screen ; molecular dynamics ; Organic chemistry ; QD241-441
Subject code	500
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Discovery and Characterization of a Cryptic Secondary Binding Site in the Molecular Chaperone HSP70.

O'Connor, Suzanne / Le Bihan, Yann-Vaï / Westwood, Isaac M / Liu, Manjuan / Mak, Oi Wei / Zazeri, Gabriel / Povinelli, Ana P R / Jones, Alan M / van Montfort, Rob / Reynisson, Jóhannes / Collins, Ian

Molecules (Basel, Switzerland)

2022 Volume 27, Issue 3

Abstract	Heat Shock Protein 70s (HSP70s) are key molecular chaperones that are overexpressed in many cancers and often associated with metastasis and poor prognosis. It has proven difficult to develop ATP-competitive, drug-like small molecule inhibitors of HSP70s due to the flexible and hydrophilic nature of the HSP70 ATP-binding site and its high affinity for endogenous nucleotides. The aim of this study was to explore the potential for the inhibition of HSP70 through alternative binding sites using fragment-based approaches. A surface plasmon resonance (SPR) fragment screen designed to detect secondary binding sites in HSP70 led to the identification by X-ray crystallography of a cryptic binding site in the nucleotide-binding domain (NBD) of HSP70 adjacent to the ATP-binding site. Fragment binding was confirmed and characterized as ATP-competitive using SPR and ligand-observed NMR methods. Molecular dynamics simulations were applied to understand the interactions with the protein upon ligand binding, and local secondary structure changes consistent with interconversion between the observed crystal structures with and without the cryptic pocket were detected. A virtual high-throughput screen (vHTS) against the cryptic pocket was conducted, and five compounds with diverse chemical scaffolds were confirmed to bind to HSP70 with micromolar affinity by SPR. These results identified and characterized a new targetable site on HSP70. While targeting HSP70 remains challenging, the new site may provide opportunities to develop allosteric ATP-competitive inhibitors with differentiated physicochemical properties from current series.
MeSH term(s)	Adenosine Triphosphate/metabolism ; Binding Sites/drug effects ; Drug Discovery ; HSP70 Heat-Shock Proteins/antagonists & inhibitors ; HSP70 Heat-Shock Proteins/chemistry ; HSP70 Heat-Shock Proteins/metabolism ; Humans ; Ligands ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Protein Domains/drug effects ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology
Chemical Substances	HSP70 Heat-Shock Proteins ; Ligands ; Small Molecule Libraries ; Adenosine Triphosphate (8L70Q75FXE)
Language	English
Publishing date	2022-01-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules27030817
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Article ; Online: Cardiac Computed Tomography Certification at Euroecho Imaging 2018.

Pontone, Gianluca / Gimelli, Alessia / Maurovich-Horvat, Pàl / Dweck, Marc R / Gaemperli, Oliver / Westwood, Mark

European heart journal cardiovascular Imaging

2019 Volume 20, Issue 3, Page(s) 253–254

MeSH term(s)	Cardiac Imaging Techniques/methods ; Certification/standards ; Clinical Competence ; Congresses as Topic ; Europe ; Female ; Humans ; Italy ; Male ; Societies, Medical ; Tomography, X-Ray Computed/methods
Language	English
Publishing date	2019-02-21
Publishing country	England
Document type	Journal Article
ZDB-ID	2638345-7
ISSN	2047-2412 ; 2047-2404
ISSN (online)	2047-2412
ISSN	2047-2404
DOI	10.1093/ehjci/jey289
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Zs.A 5614: Show issues

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Article ; Online: Preparation and Reactivity of Biomass-Derived Dihydro-Dioxins.

Montgomery, James R D / Kempf, Karl / Miles-Barrett, Daniel M / Kempf, Oxana / Lebl, Tomas / Westwood, Nicholas J

ChemSusChem

2018 Volume 12, Issue 1, Page(s) 190–193

Abstract: ... this. Heterocycles and a useful synthetic intermediate were prepared. The range of aromatics available from the β-O-4 ...

Abstract	The depolymerization of the biopolymer lignin can give pure aromatic monomers but selective catalytic approaches remain scarce. Here, an approach was rerouted to deliver an unusual phenolic monomer. This monomer's instability proved challenging, but a degradation study identified strategies to overcome this. Heterocycles and a useful synthetic intermediate were prepared. The range of aromatics available from the β-O-4 unit in lignin was extended.
Language	English
Publishing date	2018-11-05
Publishing country	Germany
Document type	Journal Article
ISSN	1864-564X
ISSN (online)	1864-564X
DOI	10.1002/cssc.201802109
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Article ; Online: NRSF/REST lies at the intersection between epigenetic regulation, miRNA-mediated gene control and neurodevelopmental pathways associated with Intellectual disability (ID) and Schizophrenia.

Alsaqati, Mouhamed / Davis, Brittany A / Wood, Jamie / Jones, Megan M / Jones, Lora / Westwood, Aishah / Petter, Olena / Isles, Anthony R / Linden, David / Van den Bree, Marianne / Owen, Michael / Hall, Jeremy / Harwood, Adrian J

Translational psychiatry

2022 Volume 12, Issue 1, Page(s) 438

Abstract: Genetic evidence indicates disrupted epigenetic regulation as a major risk factor for psychiatric disorders, but the molecular mechanisms that drive this association remain to be determined. EHMT1 is an epigenetic repressor that is causal for Kleefstra ... ...

Abstract	Genetic evidence indicates disrupted epigenetic regulation as a major risk factor for psychiatric disorders, but the molecular mechanisms that drive this association remain to be determined. EHMT1 is an epigenetic repressor that is causal for Kleefstra Syndrome (KS), a genetic disorder linked with neurodevelopmental disorders and associated with schizophrenia. Here, we show that reduced EHMT1 activity decreases NRSF/REST protein leading to abnormal neuronal gene expression and progression of neurodevelopment in human iPSC. We further show that EHMT1 regulates NRSF/REST indirectly via repression of miRNA and leads to aberrant neuronal gene regulation and neurodevelopment timing. Expression of a NRSF/REST mRNA that lacks the miRNA-binding sites restores neuronal gene regulation to EHMT1 deficient cells. Significantly, the EHMT1-regulated miRNA gene set not only controls NRSF/REST but is enriched for association for Intellectual Disability (ID) and schizophrenia. This reveals a broad molecular interaction between H3K9 demethylation, NSRF/REST regulation and risk for ID and Schizophrenia.
MeSH term(s)	Epigenesis, Genetic ; Humans ; Intellectual Disability/genetics ; MicroRNAs/genetics ; RNA, Messenger/genetics ; Repressor Proteins/genetics ; Schizophrenia/genetics
Chemical Substances	MicroRNAs ; RE1-silencing transcription factor ; RNA, Messenger ; Repressor Proteins
Language	English
Publishing date	2022-10-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2609311-X
ISSN	2158-3188 ; 2158-3188
ISSN (online)	2158-3188
ISSN	2158-3188
DOI	10.1038/s41398-022-02199-z
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Article ; Online: Lessons in cognitive unloading, skills mixing, flattened hierarchy and organisational agility from the Nightingale Hospital London during the first wave of the

Collins, George Benjamin / Ahluwalia, Nikhil / Arrol, Lynne / Forrest, Natalie / McGlennan, Alan / O'Brien, Ben / Proudfoot, Alastair / Trainer, Matthew / Schilling, Richard / Sullivan, Eamonn / Westwood, Mark / Wragg, Andrew / Knight, Charles

BMJ open quality

2021 Volume 10, Issue 3

MeSH term(s)	COVID-19/prevention & control ; Capacity Building/organization & administration ; Hospital Administration/methods ; Hospital Design and Construction/methods ; Humans ; Intensive Care Units/organization & administration ; London ; Organizational Innovation ; Personnel Selection/standards ; Personnel, Hospital/standards ; SARS-CoV-2 ; State Medicine ; Surge Capacity/organization & administration
Language	English
Publishing date	2021-07-21
Publishing country	England
Document type	Journal Article ; Review
ISSN	2399-6641
ISSN (online)	2399-6641
DOI	10.1136/bmjoq-2021-001415
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Article ; Online: Protein O-GlcNAcylation Promotes Trophoblast Differentiation at Implantation.

Ruane, Peter T / Tan, Cheryl M J / Adlam, Daman J / Kimber, Susan J / Brison, Daniel R / Aplin, John D / Westwood, Melissa

Cells

2020 Volume 9, Issue 10

Abstract: ... with O-linked β-N-acetylglucosamine (O-GlcNAcylation) is mediated by O-GlcNAc transferase and O-GlcNAcase ... OGA), and couples cellular metabolism to stress adaptation. O-GlcNAcylation is essential ... we used OGA inhibitor thiamet g (TMG) to induce raised levels of O-GlcNAcylation in mouse blastocysts and ...

Abstract	Embryo implantation begins with blastocyst trophectoderm (TE) attachment to the endometrial epithelium, followed by the breaching of this barrier by TE-derived trophoblast. Dynamic protein modification with O-linked β-N-acetylglucosamine (O-GlcNAcylation) is mediated by O-GlcNAc transferase and O-GlcNAcase (OGA), and couples cellular metabolism to stress adaptation. O-GlcNAcylation is essential for blastocyst formation, but whether there is a role for this system at implantation remains unexplored. Here, we used OGA inhibitor thiamet g (TMG) to induce raised levels of O-GlcNAcylation in mouse blastocysts and human trophoblast cells. In an in vitro embryo implantation model, TMG promoted mouse blastocyst breaching of the endometrial epithelium. TMG reduced expression of TE transcription factors
MeSH term(s)	Animals ; Cell Differentiation ; Embryo Implantation/genetics ; Female ; Humans ; Mice ; N-Acetylglucosaminyltransferases/metabolism ; Trophoblasts/metabolism
Chemical Substances	N-Acetylglucosaminyltransferases (EC 2.4.1.-) ; O-GlcNAc transferase (EC 2.4.1.-)
Language	English
Publishing date	2020-10-06
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells9102246
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Article ; Online: RadBone: bone toxicity following pelvic radiotherapy - a prospective randomised controlled feasibility study evaluating a musculoskeletal health package in women with gynaecological cancers undergoing pelvic radiotherapy.

Chatzimavridou Grigoriadou, Victoria / Barraclough, Lisa H / Baricevic-Jones, Ivona / Bristow, Robert G / Eden, Martin / Haslett, Kate / Johnson, Karen / Kochhar, Rohit / Merchant, Zoe / Moore, John / O'Connell, Sarah / Taylor, Sally / Westwood, Thomas / Whetton, Anthony David / Yorke, Janelle / Higham, Claire E

BMJ open

2022 Volume 12, Issue 6, Page(s) e056600

Abstract: Introduction: Patients receiving radiotherapy are at risk of developing radiotherapy-related insufficiency fractures, which are associated with increased morbidity and pose a significant burden to patients' quality of life and to the health system. ... ...

Abstract	Introduction: Patients receiving radiotherapy are at risk of developing radiotherapy-related insufficiency fractures, which are associated with increased morbidity and pose a significant burden to patients' quality of life and to the health system. Therefore, effective preventive techniques are urgently required. The RadBone randomised controlled trial (RCT) aims to determine the feasibility and acceptability of a musculoskeletal health package (MHP) intervention in women undergoing pelvic radiotherapy for gynaecological malignancies and to preliminary explore clinical effectiveness of the intervention. Methods and analysis: The RadBone RCT will evaluate the addition to standard care of an MHP consisting of a physical assessment of the musculoskeletal health, a 3-month prehabilitation personalised exercise package, as well as an evaluation of the fracture risk and if required the prescription of appropriate bone treatment including calcium, vitamin D and-for high-risk individuals-bisphosphonates. Forty participants will be randomised in each group (MHP or observation) and will be followed for 18 months. The primary outcome of this RCT will be feasibility, including the eligibility, screening and recruitment rate, intervention fidelity and attrition rates; acceptability and health economics. Clinical effectiveness and bone turnover markers will be evaluated as secondary outcomes. Ethics and dissemination: This study has been approved by the Greater Manchester East Research Ethics Committee (Reference: 20/NW/0410, November 2020). The results will be published in peer-reviewed journals, will be presented in national and international conferences and will be communicated to relevant stakeholders. Moreover, a plain English report will be shared with the study participants, patients' organisations and media. Trial registration number: NCT04555317.
MeSH term(s)	Diphosphonates ; Feasibility Studies ; Female ; Genital Neoplasms, Female/radiotherapy ; Humans ; Prospective Studies ; Research Design
Chemical Substances	Diphosphonates
Language	English
Publishing date	2022-06-14
Publishing country	England
Document type	Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	2599832-8
ISSN	2044-6055 ; 2044-6055
ISSN (online)	2044-6055
ISSN	2044-6055
DOI	10.1136/bmjopen-2021-056600
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Article ; Online: A tubulin binding molecule drives differentiation of acute myeloid leukemia cells

iScience, Vol 25, Iss 8, Pp 104787- (2022)

2022

Abstract: ... that cause differentiation by inducing a G2-M mitotic arrest. Together, these results reveal a function ...

Abstract	Summary: Despite much progress in developing better drugs, many patients with acute myeloid leukemia (AML) still die within a year of diagnosis. This is partly because it is difficult to identify therapeutic targets that are effective across multiple AML subtypes. One common factor across AML subtypes is the presence of a block in differentiation. Overcoming this block should allow for the identification of therapies that are not dependent on a specific mutation for their efficacy. Here, we used a phenotypic screen to identify compounds that stimulate differentiation in genetically diverse AML cell lines. Lead compounds were shown to decrease tumor burden and to increase survival in vivo. Using multiple complementary target deconvolution approaches, these compounds were revealed to be anti-mitotic tubulin disruptors that cause differentiation by inducing a G2-M mitotic arrest. Together, these results reveal a function for tubulin disruptors in causing differentiation of AML cells.
Keywords	Chemistry ; Biological sciences ; Molecular biology ; Molecular medicine ; Cancer ; Science ; Q
Language	English
Publishing date	2022-08-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Guidelines for training in cardiovascular magnetic resonance (CMR).

Kim, R J / Simonetti, O P / Westwood, M / Kramer, C M / Narang, A / Friedrich, M G / Powell, A J / Carr, J C / Schulz-Menger, J / Nagel, E / Chan, W S / Bremerich, J / Ordovas, K G / Rollings, R C / Patel, A R / Ferrari, V A

Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance

2018 Volume 20, Issue 1, Page(s) 57

Abstract: These "Guidelines for training in Cardiovascular Magnetic Resonance" were developed by the Certification Committee of the Society for Cardiovascular Magnetic Resonance (SCMR) and approved by the SCMR Board of Trustees. ...

Abstract	These "Guidelines for training in Cardiovascular Magnetic Resonance" were developed by the Certification Committee of the Society for Cardiovascular Magnetic Resonance (SCMR) and approved by the SCMR Board of Trustees.
MeSH term(s)	Cardiology/education ; Cardiology/standards ; Certification/methods ; Certification/standards ; Clinical Competence ; Curriculum ; Education, Medical, Graduate/methods ; Education, Medical, Graduate/standards ; Humans ; Internship and Residency/standards ; Magnetic Resonance Imaging
Language	English
Publishing date	2018-08-16
Publishing country	England
Document type	Guideline ; Journal Article
ZDB-ID	1458034-2
ISSN	1532-429X ; 1097-6647
ISSN (online)	1532-429X
ISSN	1097-6647
DOI	10.1186/s12968-018-0481-8
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Zs.A 5045: Show issues

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