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Article ; Online: Extending the Code of Sequence Readout by Gene Regulatory Proteins: The Role of Hoogsteen Base Pairing in p53-DNA Recognition.

Joerger, Andreas C

Structure (London, England : 1993)

2018 Volume 26, Issue 9, Page(s) 1163–1165

Abstract: The tumor suppressor p53 regulates the transcription of a myriad of target genes. In this issue of Structure, Golovenko et al. (2018) elucidate the role of non-canonical Hoogsteen A/T base pairs in p53-DNA recognition, highlighting DNA shape as an ... ...

Abstract	The tumor suppressor p53 regulates the transcription of a myriad of target genes. In this issue of Structure, Golovenko et al. (2018) elucidate the role of non-canonical Hoogsteen A/T base pairs in p53-DNA recognition, highlighting DNA shape as an additional layer of sequence readout.
MeSH term(s)	Base Pairing ; DNA ; Tumor Suppressor Protein p53
Chemical Substances	Tumor Suppressor Protein p53 ; DNA (9007-49-2)
Language	English
Publishing date	2018-09-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	1213087-4
ISSN	1878-4186 ; 0969-2126
ISSN (online)	1878-4186
ISSN	0969-2126
DOI	10.1016/j.str.2018.08.008
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Article ; Online: Structural insights into a regulatory mechanism of FIR RRM1-FUSE interaction.

Ni, Xiaomin / Joerger, Andreas C / Chaikuad, Apirat / Knapp, Stefan

Open biology

2023 Volume 13, Issue 5, Page(s) 230031

Abstract: FUBP-interacting repressor (FIR) is a suppressor of transcription of the proto-oncogene MYC. FIR binds to the far upstream element (FUSE) of the MYC promoter. Competition of FIR with FUSE-binding protein 1 (FUBP1) is a key mechanism of MYC ... ...

Abstract	FUBP-interacting repressor (FIR) is a suppressor of transcription of the proto-oncogene MYC. FIR binds to the far upstream element (FUSE) of the MYC promoter. Competition of FIR with FUSE-binding protein 1 (FUBP1) is a key mechanism of MYC transcriptional regulation. To gain insights into the structural mechanisms regulating FIR DNA interaction, we determined the crystal structure of two FIR RRM domains (RRM1-2) with single-stranded FUSE DNA sequences. These structures revealed an ability of the RRM domain to recognize diverse FUSE regions through distinct intermolecular interactions and binding modes. Comparative structural analyses against available RRM-ssDNA/RNA complexes showed that the nucleotide configurations in FIR were similar to those in other RRMs that harbour a tyrosine at the conserved aromatic position in the RNP2 motif (Y-type RRM), but not those with a phenylalanine (F-type RRM). Site-directed mutagenesis experiments demonstrated that a single substitution, Y115F, altered the binding affinities of oligonucleotides to FIR RRM, suggesting an important role of this conserved aromatic residue in ssDNA/RNA interactions. Our study provides the structural basis for further mechanistic studies on this important protein-DNA interaction.
MeSH term(s)	RNA Splicing Factors ; Repressor Proteins/metabolism ; Protein Binding ; RNA/metabolism ; DNA/metabolism
Chemical Substances	RNA Splicing Factors ; Repressor Proteins ; RNA (63231-63-0) ; DNA (9007-49-2)
Language	English
Publishing date	2023-05-31
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2630944-0
ISSN	2046-2441 ; 2046-2441
ISSN (online)	2046-2441
ISSN	2046-2441
DOI	10.1098/rsob.230031
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Article ; Online: Structural insights into a regulatory mechanism of FIR RRM1–FUSE interaction

Xiaomin Ni / Andreas C. Joerger / Apirat Chaikuad / Stefan Knapp

Open Biology, Vol 13, Iss

2023 Volume 5

Abstract	FUBP-interacting repressor (FIR) is a suppressor of transcription of the proto-oncogene MYC. FIR binds to the far upstream element (FUSE) of the MYC promoter. Competition of FIR with FUSE-binding protein 1 (FUBP1) is a key mechanism of MYC transcriptional regulation. To gain insights into the structural mechanisms regulating FIR DNA interaction, we determined the crystal structure of two FIR RRM domains (RRM1-2) with single-stranded FUSE DNA sequences. These structures revealed an ability of the RRM domain to recognize diverse FUSE regions through distinct intermolecular interactions and binding modes. Comparative structural analyses against available RRM-ssDNA/RNA complexes showed that the nucleotide configurations in FIR were similar to those in other RRMs that harbour a tyrosine at the conserved aromatic position in the RNP2 motif (Y-type RRM), but not those with a phenylalanine (F-type RRM). Site-directed mutagenesis experiments demonstrated that a single substitution, Y115F, altered the binding affinities of oligonucleotides to FIR RRM, suggesting an important role of this conserved aromatic residue in ssDNA/RNA interactions. Our study provides the structural basis for further mechanistic studies on this important protein–DNA interaction.
Keywords	RNA recognition motif (RRM) ; RNP2 motif ; nucleotide configuration ; Biology (General) ; QH301-705.5
Subject code	500
Language	English
Publishing date	2023-05-01T00:00:00Z
Publisher	The Royal Society
Document type	Article ; Online
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Article ; Online: Exploiting vulnerabilities of SWI/SNF chromatin remodelling complexes for cancer therapy.

Wanior, Marek / Krämer, Andreas / Knapp, Stefan / Joerger, Andreas C

Oncogene

2021 Volume 40, Issue 21, Page(s) 3637–3654

Abstract: Multi-subunit ATPase-dependent chromatin remodelling complexes SWI/SNF (switch/sucrose non-fermentable) are fundamental epigenetic regulators of gene transcription. Functional genomic studies revealed a remarkable mutation prevalence of SWI/SNF-encoding ... ...

Abstract	Multi-subunit ATPase-dependent chromatin remodelling complexes SWI/SNF (switch/sucrose non-fermentable) are fundamental epigenetic regulators of gene transcription. Functional genomic studies revealed a remarkable mutation prevalence of SWI/SNF-encoding genes in 20-25% of all human cancers, frequently driving oncogenic programmes. Some SWI/SNF-mutant cancers are hypersensitive to perturbations in other SWI/SNF subunits, regulatory proteins and distinct biological pathways, often resulting in sustained anticancer effects and synthetic lethal interactions. Exploiting these vulnerabilities is a promising therapeutic strategy. Here, we review the importance of SWI/SNF chromatin remodellers in gene regulation as well as mechanisms leading to assembly defects and their role in cancer development. We will focus in particular on emerging strategies for the targeted therapy of SWI/SNF-deficient cancers using chemical probes, including proteolysis targeting chimeras, to induce synthetic lethality.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Carcinogenesis ; Chromatin Assembly and Disassembly ; Chromosomal Proteins, Non-Histone/antagonists & inhibitors ; Epigenomics ; Humans ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/metabolism ; Neoplasms/pathology ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	Antineoplastic Agents ; Chromosomal Proteins, Non-Histone ; Transcription Factors
Language	English
Publishing date	2021-05-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	639046-8
ISSN	1476-5594 ; 0950-9232
ISSN (online)	1476-5594
ISSN	0950-9232
DOI	10.1038/s41388-021-01781-x
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Article: Back-pocket optimization of 2-aminopyrimidine-based macrocycles leads to potent dual EPHA2/GAK kinase inhibitors with antiviral activity.

Gerninghaus, Joshua / Zhubi, Rezart / Krämer, Andreas / Karim, Marwah / Tran, Do Hoang Nhu / Joerger, Andreas C / Schreiber, Christian / Berger, Lena M / Berger, Benedict-Tilman / Ehret, Theresa A L / Elson, Lewis / Lenz, Christopher / Saxena, Krishna / Müller, Susanne / Einav, Shirit / Knapp, Stefan / Hanke, Thomas

bioRxiv : the preprint server for biology

2024

Abstract: Macrocyclization of acyclic compounds is a powerful strategy for improving inhibitor potency and selectivity. Here, we developed a 2-aminopyrimidine-based macrocyclic dual EPHA2/GAK kinase inhibitor as a chemical tool to study the role of these two ... ...

Abstract	Macrocyclization of acyclic compounds is a powerful strategy for improving inhibitor potency and selectivity. Here, we developed a 2-aminopyrimidine-based macrocyclic dual EPHA2/GAK kinase inhibitor as a chemical tool to study the role of these two kinases in viral entry and assembly. Starting with a promiscuous macrocyclic inhibitor,
Language	English
Publishing date	2024-02-18
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.02.18.580805
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Article ; Online: Development of Selective Pyrido[2,3-

Rak, Marcel / Menge, Amelie / Tesch, Roberta / Berger, Lena M / Balourdas, Dimitrios-Ilias / Shevchenko, Ekaterina / Krämer, Andreas / Elson, Lewis / Berger, Benedict-Tilman / Abdi, Ismahan / Wahl, Laurenz M / Poso, Antti / Kaiser, Astrid / Hanke, Thomas / Kronenberger, Thales / Joerger, Andreas C / Müller, Susanne / Knapp, Stefan

Journal of medicinal chemistry

2024 Volume 67, Issue 5, Page(s) 3813–3842

Abstract: Mammalian STE20-like (MST) kinases 1-4 play key roles in regulating the Hippo and autophagy pathways, and their dysregulation has been implicated in cancer development. In contrast to the well-studied MST1/2, the roles of MST3/4 are less clear, in part ... ...

Abstract	Mammalian STE20-like (MST) kinases 1-4 play key roles in regulating the Hippo and autophagy pathways, and their dysregulation has been implicated in cancer development. In contrast to the well-studied MST1/2, the roles of MST3/4 are less clear, in part due to the lack of potent and selective inhibitors. Here, we re-evaluated literature compounds, and used structure-guided design to optimize the p21-activated kinase (PAK) inhibitor G-5555 (
MeSH term(s)	Animals ; Protein Serine-Threonine Kinases/metabolism ; p21-Activated Kinases ; Mammals/metabolism
Chemical Substances	Protein Serine-Threonine Kinases (EC 2.7.11.1) ; p21-Activated Kinases (EC 2.7.11.1)
Language	English
Publishing date	2024-02-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.3c02217
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Article ; Online: Development of Potent Dual BET/HDAC Inhibitors via Pharmacophore Merging and Structure-Guided Optimization.

Bauer, Nicolas / Balourdas, Dimitrios-Ilias / Schneider, Joel R / Zhang, Xin / Berger, Lena M / Berger, Benedict-Tilman / Schwalm, Martin P / Klopp, Nick A / Siveke, Jens T / Knapp, Stefan / Joerger, Andreas C

ACS chemical biology

2024 Volume 19, Issue 2, Page(s) 266–279

Abstract: Bromodomain and extra-terminal domain (BET) proteins and histone deacetylases (HDACs) are prime targets in cancer therapy. Recent research has particularly focused on the development of dual BET/HDAC inhibitors for hard-to-treat tumors, such as ... ...

Abstract	Bromodomain and extra-terminal domain (BET) proteins and histone deacetylases (HDACs) are prime targets in cancer therapy. Recent research has particularly focused on the development of dual BET/HDAC inhibitors for hard-to-treat tumors, such as pancreatic cancer. Here, we developed a new series of potent dual BET/HDAC inhibitors by choosing starting scaffolds that enabled us to optimally merge the two functionalities into a single compound. Systematic structure-guided modification of both warheads then led to optimized binders that were superior in potency to both parent compounds, with the best molecules of this series binding to both BRD4 bromodomains as well as HDAC1/2 with EC
MeSH term(s)	Humans ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylase Inhibitors/chemistry ; Nuclear Proteins/metabolism ; Transcription Factors/metabolism ; Pharmacophore ; Pancreatic Neoplasms/drug therapy ; Carcinoma ; Cell Line, Tumor ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/chemistry ; RNA-Binding Proteins ; Bromodomain Containing Proteins ; Cell Cycle Proteins/metabolism
Chemical Substances	Histone Deacetylase Inhibitors ; Nuclear Proteins ; Transcription Factors ; Antineoplastic Agents ; HEXIM1 protein, human ; RNA-Binding Proteins ; BRD4 protein, human ; Bromodomain Containing Proteins ; Cell Cycle Proteins
Language	English
Publishing date	2024-01-31
Publishing country	United States
Document type	Journal Article
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/acschembio.3c00427
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Article ; Online: Synthesis of Pyrazole-Based Macrocycles Leads to a Highly Selective Inhibitor for MST3.

Amrhein, Jennifer Alisa / Berger, Lena Marie / Balourdas, Dimitrios-Ilias / Joerger, Andreas C / Menge, Amelie / Krämer, Andreas / Frischkorn, Julia Marie / Berger, Benedict-Tilman / Elson, Lewis / Kaiser, Astrid / Schubert-Zsilavecz, Manfred / Müller, Susanne / Knapp, Stefan / Hanke, Thomas

Journal of medicinal chemistry

2023 Volume 67, Issue 1, Page(s) 674–690

Abstract: MST1, MST2, MST3, MST4, and YSK1 are conserved members of the mammalian sterile 20-like serine/threonine (MST) family that regulate cellular functions such as proliferation and migration. The MST3 isozyme plays a role in regulating cell growth and ... ...

Abstract	MST1, MST2, MST3, MST4, and YSK1 are conserved members of the mammalian sterile 20-like serine/threonine (MST) family that regulate cellular functions such as proliferation and migration. The MST3 isozyme plays a role in regulating cell growth and apoptosis, and its dysregulation has been linked to high-grade tumors. To date, there are no isoform-selective inhibitors that could be used for validating the role of MST3 in tumorigenesis. We designed a series of 3-aminopyrazole-based macrocycles based on the structure of a promiscuous inhibitor. By varying the moieties targeting the solvent-exposed region and optimizing the linker, macrocycle JA310 (
MeSH term(s)	Animals ; Protein Serine-Threonine Kinases/metabolism ; Phosphorylation ; Apoptosis ; Mammals/metabolism
Chemical Substances	Protein Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2023-12-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.3c01980
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Article ; Online: Integrated analysis of Shank1 PDZ interactions with C-terminal and internal binding motifs.

Ali, Muhammad / McAuley, Mishal Mariam / Lüchow, Susanne / Knapp, Stefan / Joerger, Andreas C / Ivarsson, Ylva

Current research in structural biology

2021 Volume 3, Page(s) 41–50

Abstract: PDZ domains constitute a large family of modular domains that are well-known for binding C-terminal ... using the PDZ domain of Shank1 as a model. We identified a series of human Shank1 ligands with C ... that while the consensus sequence of C-terminal ligands is x-T-x-(L/F)-COOH, the consensus of internal PDZbm is exclusively x-T-x-F ...

Abstract	PDZ domains constitute a large family of modular domains that are well-known for binding C-terminal motifs of target proteins. Some of them also bind to internal PDZ binding motifs (PDZbms), but this aspect of the PDZ interactome is poorly studied. Here we explored internal PDZbm-mediated interactions using the PDZ domain of Shank1 as a model. We identified a series of human Shank1 ligands with C-terminal or internal PDZbms using proteomic peptide-phage display, and established that while the consensus sequence of C-terminal ligands is x-T-x-(L/F)-COOH, the consensus of internal PDZbm is exclusively x-T-x-F-x, where x is any amino acid. We found that the affinities of PDZbm interactions are in the low micromolar range. The crystal structure of the complex between Shank1 PDZ and an internal PDZbm revealed that the binding mode of internal PDZbms was similar to that of C-terminal ligands. Pull-down experiments confirmed that both C-terminal and internal PDZbm interactions can occur in the context of full-length proteins. Our study expands the interactome of Shank1 and hints at a largely unexplored interaction space of PDZ domains.
Language	English
Publishing date	2021-01-05
Publishing country	Netherlands
Document type	Journal Article
ISSN	2665-928X
ISSN (online)	2665-928X
DOI	10.1016/j.crstbi.2021.01.001
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Article ; Online: The p53 Pathway: Origins, Inactivation in Cancer, and Emerging Therapeutic Approaches.

Joerger, Andreas C / Fersht, Alan R

Annual review of biochemistry

2016 Volume 85, Page(s) 375–404

Abstract: Inactivation of the transcription factor p53, through either direct mutation or aberrations in one of its many regulatory pathways, is a hallmark of virtually every tumor. In recent years, screening for p53 activators and a better understanding of the ... ...

Abstract	Inactivation of the transcription factor p53, through either direct mutation or aberrations in one of its many regulatory pathways, is a hallmark of virtually every tumor. In recent years, screening for p53 activators and a better understanding of the molecular mechanisms of oncogenic perturbations of p53 function have opened up a host of novel avenues for therapeutic intervention in cancer: from the structure-guided design of chemical chaperones to restore the function of conformationally unstable p53 cancer mutants, to the development of potent antagonists of the negative regulators MDM2 and MDMX and other modulators of the p53 pathway for the treatment of cancers with wild-type p53. Some of these compounds have now moved from proof-of-concept studies into clinical trials, with prospects for further, personalized anticancer medicines. We trace the structural evolution of the p53 pathway, from germ-line surveillance in simple multicellular organisms to its pluripotential role in humans.
MeSH term(s)	Animals ; Antineoplastic Agents, Alkylating/chemical synthesis ; Antineoplastic Agents, Alkylating/therapeutic use ; Cell Cycle Proteins ; Clinical Trials as Topic ; Drug Design ; Gene Expression Regulation, Neoplastic ; Humans ; Molecular Docking Simulation ; Molecular Targeted Therapy ; Mutation ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/metabolism ; Neoplasms/pathology ; Nuclear Proteins/antagonists & inhibitors ; Nuclear Proteins/chemistry ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Protein Multimerization ; Protein Structure, Secondary ; Proto-Oncogene Proteins/antagonists & inhibitors ; Proto-Oncogene Proteins/chemistry ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors ; Proto-Oncogene Proteins c-mdm2/chemistry ; Proto-Oncogene Proteins c-mdm2/genetics ; Proto-Oncogene Proteins c-mdm2/metabolism ; Signal Transduction ; Tumor Suppressor Protein p53/agonists ; Tumor Suppressor Protein p53/chemistry ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	Antineoplastic Agents, Alkylating ; Cell Cycle Proteins ; MDM4 protein, human ; Nuclear Proteins ; Proto-Oncogene Proteins ; Tumor Suppressor Protein p53 ; MDM2 protein, human (EC 2.3.2.27) ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27)
Language	English
Publishing date	2016-05-04
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	207924-0
ISSN	1545-4509 ; 0066-4154
ISSN (online)	1545-4509
ISSN	0066-4154
DOI	10.1146/annurev-biochem-060815-014710
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