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Article ; Online: Discovery, X-ray Crystallography, and Anti-inflammatory Activity of Bromodomain-containing Protein 4 (BRD4) BD1 Inhibitors Targeting a Distinct New Binding Site.

Liu, Zhiqing / Li, Yi / Chen, Haiying / Lai, Hsien-Tsung / Wang, Pingyuan / Wu, Shwu-Yuan / Wold, Eric A / Leonard, Paul G / Joseph, Sarah / Hu, Haitao / Chiang, Cheng-Ming / Brasier, Allan R / Tian, Bing / Zhou, Jia

Journal of medicinal chemistry

2022 Volume 65, Issue 3, Page(s) 2388–2408

Abstract: Bromodomain-containing protein 4 (BRD4) is an emerging epigenetic drug target for intractable inflammatory disorders. The lack of highly selective inhibitors among BRD4 family members has stalled the collective understanding of this critical system and ... ...

Abstract	Bromodomain-containing protein 4 (BRD4) is an emerging epigenetic drug target for intractable inflammatory disorders. The lack of highly selective inhibitors among BRD4 family members has stalled the collective understanding of this critical system and the progress toward clinical development of effective therapeutics. Here we report the discovery of a potent BRD4 bromodomain 1 (BD1)-selective inhibitor ZL0590 (
MeSH term(s)	Animals ; Anti-Inflammatory Agents/chemical synthesis ; Anti-Inflammatory Agents/metabolism ; Anti-Inflammatory Agents/pharmacokinetics ; Anti-Inflammatory Agents/pharmacology ; Binding Sites ; Cell Cycle Proteins/antagonists & inhibitors ; Cell Cycle Proteins/metabolism ; Cell Line ; Crystallography, X-Ray ; Gene Expression/drug effects ; Humans ; Interleukin-6/genetics ; Interleukin-6/metabolism ; Male ; Mice, Inbred C57BL ; Nuclear Proteins/antagonists & inhibitors ; Oxidoreductases Acting on CH-CH Group Donors/genetics ; Oxidoreductases Acting on CH-CH Group Donors/metabolism ; Phenylurea Compounds/chemical synthesis ; Phenylurea Compounds/metabolism ; Phenylurea Compounds/pharmacokinetics ; Phenylurea Compounds/pharmacology ; Protein Binding ; Protein Domains ; Rats ; Transcription Factors/antagonists & inhibitors ; Transcription Factors/metabolism ; Mice
Chemical Substances	Anti-Inflammatory Agents ; BRD4 protein, human ; Brd4 protein, mouse ; Cell Cycle Proteins ; IL6 protein, human ; Interleukin-6 ; Nuclear Proteins ; Phenylurea Compounds ; Transcription Factors ; Oxidoreductases Acting on CH-CH Group Donors (EC 1.3.-) ; RSAD2 protein, human (EC 1.3.-)
Language	English
Publishing date	2022-01-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.1c01851
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Article ; Online: GRB2 enforces homology-directed repair initiation by MRE11.

Ye, Zu / Xu, Shengfeng / Shi, Yin / Bacolla, Albino / Syed, Aleem / Moiani, Davide / Tsai, Chi-Lin / Shen, Qiang / Peng, Guang / Leonard, Paul G / Jones, Darin E / Wang, Bin / Tainer, John A / Ahmed, Zamal

Science advances

2021 Volume 7, Issue 32

Abstract: DNA double-strand break (DSB) repair is initiated by MRE11 nuclease for both homology-directed repair (HDR) and alternative end joining (Alt-EJ). Here, we found that GRB2, crucial to timely proliferative RAS/MAPK pathway activation, unexpectedly forms a ... ...

Abstract	DNA double-strand break (DSB) repair is initiated by MRE11 nuclease for both homology-directed repair (HDR) and alternative end joining (Alt-EJ). Here, we found that GRB2, crucial to timely proliferative RAS/MAPK pathway activation, unexpectedly forms a biophysically validated GRB2-MRE11 (GM) complex for efficient HDR initiation. GRB2-SH2 domain targets the GM complex to phosphorylated H2AX at DSBs. GRB2 K109 ubiquitination by E3 ubiquitin ligase RBBP6 releases MRE11 promoting HDR. RBBP6 depletion results in prolonged GM complex and HDR defects. GRB2 knockout increased MRE11-XRCC1 complex and Alt-EJ. Reconstitution with separation-of-function GRB2 mutant caused HDR deficiency and synthetic lethality with PARP inhibitor. Cell and cancer genome analyses suggest biomarkers of low GRB2 for noncanonical HDR deficiency and high MRE11 and GRB2 expression for worse survival in HDR-proficient patients. These findings establish GRB2's role in binding, targeting, and releasing MRE11 to promote efficient HDR over Alt-EJ DSB repair, with implications for genome stability and cancer biology.
Language	English
Publishing date	2021-08-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.abe9254
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Article ; Online: Phosphorylation-dependent conformational changes and domain rearrangements in Staphylococcus aureus VraR activation.

Leonard, Paul G / Golemi-Kotra, Dasantila / Stock, Ann M

Proceedings of the National Academy of Sciences of the United States of America

2013 Volume 110, Issue 21, Page(s) 8525–8530

Abstract: Staphylococcus aureus VraR, a vancomycin-resistance-associated response regulator, activates a cell-wall-stress stimulon in response to antibiotics that inhibit cell wall formation. X-ray crystal structures of VraR in both unphosphorylated and ... ...

Abstract	Staphylococcus aureus VraR, a vancomycin-resistance-associated response regulator, activates a cell-wall-stress stimulon in response to antibiotics that inhibit cell wall formation. X-ray crystal structures of VraR in both unphosphorylated and beryllofluoride-activated states have been determined, revealing a mechanism of phosphorylation-induced dimerization that features a deep hydrophobic pocket at the center of the receiver domain interface. Unphosphorylated VraR exists in a closed conformation that inhibits dimer formation. Phosphorylation at the active site promotes conformational changes that are propagated throughout the receiver domain, promoting the opening of a hydrophobic pocket that is essential for homodimer formation and enhanced DNA-binding activity. This prominent feature in the VraR dimer can potentially be exploited for the development of novel therapeutics to counteract antibiotic resistance in this important pathogen.
MeSH term(s)	Bacterial Proteins/chemistry ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Crystallography, X-Ray ; DNA-Binding Proteins/chemistry ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Drug Resistance, Bacterial/physiology ; Phosphorylation/physiology ; Protein Multimerization ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Staphylococcus aureus/chemistry ; Staphylococcus aureus/genetics ; Staphylococcus aureus/metabolism
Chemical Substances	Bacterial Proteins ; DNA-Binding Proteins ; VraR protein, Staphylococcus aureus
Language	English
Publishing date	2013-05-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1302819110
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Article ; Online: Discovery of Orally Bioavailable Chromone Derivatives as Potent and Selective BRD4 Inhibitors: Scaffold Hopping, Optimization, and Pharmacological Evaluation.

Liu, Zhiqing / Chen, Haiying / Wang, Pingyuan / Li, Yi / Wold, Eric A / Leonard, Paul G / Joseph, Sarah / Brasier, Allan R / Tian, Bing / Zhou, Jia

Journal of medicinal chemistry

2020 Volume 63, Issue 10, Page(s) 5242–5256

Abstract: Bromodomain-containing protein 4 (BRD4) represents a promising drug target for anti-inflammatory therapeutics. Herein, we report the design, synthesis, and pharmacological evaluation of novel chromone derivatives via scaffold hopping to discover a new ... ...

Abstract	Bromodomain-containing protein 4 (BRD4) represents a promising drug target for anti-inflammatory therapeutics. Herein, we report the design, synthesis, and pharmacological evaluation of novel chromone derivatives via scaffold hopping to discover a new class of orally bioavailable BRD4-selective inhibitors. Two potent BRD4 bromodomain 1 (BD1)-selective inhibitors
MeSH term(s)	Administration, Oral ; Animals ; Biological Availability ; Cell Cycle Proteins/antagonists & inhibitors ; Cell Cycle Proteins/metabolism ; Cell Line, Transformed ; Chromones/administration & dosage ; Chromones/chemistry ; Chromones/pharmacology ; Crystallization/methods ; Crystallization/trends ; Drug Discovery/methods ; Drug Discovery/trends ; Drug Evaluation, Preclinical/methods ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Structure-Activity Relationship ; Transcription Factors/antagonists & inhibitors ; Transcription Factors/metabolism
Chemical Substances	BRD4 protein, human ; Cell Cycle Proteins ; Chromones ; Transcription Factors
Language	English
Publishing date	2020-04-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.0c00035
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Article ; Online: Identification of a hydrophobic cleft in the LytTR domain of AgrA as a locus for small molecule interactions that inhibit DNA binding.

Leonard, Paul G / Bezar, Ian F / Sidote, David J / Stock, Ann M

Biochemistry

2012 Volume 51, Issue 50, Page(s) 10035–10043

Abstract: The AgrA transcription factor regulates the quorum-sensing response in Staphylococcus aureus, controlling the production of hemolysins and other virulence factors. AgrA binds to DNA via its C-terminal LytTR domain, a domain not found in humans but common ...

Abstract	The AgrA transcription factor regulates the quorum-sensing response in Staphylococcus aureus, controlling the production of hemolysins and other virulence factors. AgrA binds to DNA via its C-terminal LytTR domain, a domain not found in humans but common in many pathogenic bacteria, making it a potential target for antimicrobial development. We have determined the crystal structure of the apo AgrA LytTR domain and screened a library of 500 fragment compounds to find inhibitors of AgrA DNA binding activity. Using nuclear magnetic resonance, the binding site for five compounds has been mapped to a common locus at the C-terminal end of the LytTR domain, a site known to be important for DNA binding activity. Three of these compounds inhibit AgrA DNA binding. These results provide the first evidence that LytTR domains can be targeted by small organic compounds.
MeSH term(s)	Bacterial Proteins/antagonists & inhibitors ; Bacterial Proteins/chemistry ; Crystallization ; Crystallography, X-Ray ; DNA-Binding Proteins/chemistry ; Hydrophobic and Hydrophilic Interactions ; Molecular Docking Simulation ; Nuclear Magnetic Resonance, Biomolecular ; Peptide Library ; Peptides, Cyclic/antagonists & inhibitors ; Peptides, Cyclic/chemistry ; Protein Structure, Tertiary/drug effects ; Quorum Sensing/drug effects ; Staphylococcus aureus/genetics
Chemical Substances	AgrD protein, Staphylococcus ; Bacterial Proteins ; DNA-Binding Proteins ; Peptide Library ; Peptides, Cyclic
Language	English
Publishing date	2012-12-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/bi3011785
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Article ; Online: The 3

Pisaneschi, Federica / Lin, Yu-Hsi / Leonard, Paul G / Satani, Nikunj / Yan, Victoria C / Hammoudi, Naima / Raghavan, Sudhir / Link, Todd M / K Georgiou, Dimitra / Czako, Barbara / Muller, Florian L

Molecules (Basel, Switzerland)

2019 Volume 24, Issue 13

Abstract: We recently reported that SF2312 ((1,5-dihydroxy-2-oxopyrrolidin-3-yl)phosphonic acid), a phosphonate antibiotic with a previously unknown mode of action, is a potent inhibitor of the glycolytic enzyme, Enolase. SF2312 can only be synthesized as a ... ...

Abstract	We recently reported that SF2312 ((1,5-dihydroxy-2-oxopyrrolidin-3-yl)phosphonic acid), a phosphonate antibiotic with a previously unknown mode of action, is a potent inhibitor of the glycolytic enzyme, Enolase. SF2312 can only be synthesized as a racemic-diastereomeric mixture. However, co-crystal structures with Enolase 2 (ENO2) have consistently shown that only the (3
MeSH term(s)	Binding Sites ; Enzyme Activation/drug effects ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Models, Molecular ; Molecular Conformation ; Molecular Structure ; Organophosphonates/chemistry ; Organophosphonates/pharmacology ; Phosphopyruvate Hydratase/antagonists & inhibitors ; Phosphopyruvate Hydratase/chemistry ; Protein Binding ; Pyrrolidinones/chemistry ; Pyrrolidinones/pharmacology ; Spectrum Analysis ; Stereoisomerism ; Structure-Activity Relationship
Chemical Substances	(1,5-dihydroxy-2-oxopyrrolidin-3-yl)phosphonic acid ; Enzyme Inhibitors ; Organophosphonates ; Pyrrolidinones ; Phosphopyruvate Hydratase (EC 4.2.1.11)
Language	English
Publishing date	2019-07-09
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/molecules24132510
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Article ; Online: An Adaptive Mutation in Enterococcus faecium LiaR Associated with Antimicrobial Peptide Resistance Mimics Phosphorylation and Stabilizes LiaR in an Activated State.

Davlieva, Milya / Tovar-Yanez, Angel / DeBruler, Kimberly / Leonard, Paul G / Zianni, Michael R / Arias, Cesar A / Shamoo, Yousif

Journal of molecular biology

2016 Volume 428, Issue 22, Page(s) 4503–4519

Abstract: The cyclic antimicrobial lipopeptide daptomycin (DAP) triggers the LiaFSR membrane stress response pathway in enterococci and many other Gram-positive organisms. LiaR is the response regulator that, upon phosphorylation, binds in a sequence-specific ... ...

Abstract	The cyclic antimicrobial lipopeptide daptomycin (DAP) triggers the LiaFSR membrane stress response pathway in enterococci and many other Gram-positive organisms. LiaR is the response regulator that, upon phosphorylation, binds in a sequence-specific manner to DNA to regulate transcription in response to membrane stress. In clinical settings, non-susceptibility to DAP by Enterococcus faecium is correlated frequently with a mutation in LiaR of Trp73 to Cys (LiaR
MeSH term(s)	Adaptation, Biological ; Anti-Bacterial Agents/pharmacology ; Bacterial Proteins/chemistry ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Crystallography, X-Ray ; DNA, Bacterial/metabolism ; Daptomycin/pharmacology ; Drug Resistance, Bacterial ; Enterococcus faecium/drug effects ; Enterococcus faecium/genetics ; Gene Expression Regulation, Bacterial ; Magnetic Resonance Spectroscopy ; Models, Molecular ; Mutant Proteins/chemistry ; Mutant Proteins/genetics ; Mutant Proteins/metabolism ; Mutation ; Operon ; Phosphorylation ; Promoter Regions, Genetic ; Protein Binding ; Protein Conformation ; Protein Multimerization ; Protein Processing, Post-Translational ; Transcription Factors/chemistry ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Transcription, Genetic
Chemical Substances	Anti-Bacterial Agents ; Bacterial Proteins ; DNA, Bacterial ; Mutant Proteins ; Transcription Factors ; Daptomycin (NWQ5N31VKK)
Language	English
Publishing date	2016-11-06
Publishing country	England
Document type	Journal Article
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2016.09.016
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Article: Identification of a Hydrophobic Cleft in the LytTR Domain of AgrA as a Locus for Small Molecule Interactions That Inhibit DNA Binding

Leonard, Paul G / Bezar Ian F / Sidote David J / Stock Ann M

Biochemistry. 2012 Dec. 18, v. 51, no. 50

2012

Abstract	The AgrA transcription factor regulates the quorum-sensing response in Staphylococcus aureus, controlling the production of hemolysins and other virulence factors. AgrA binds to DNA via its C-terminal LytTR domain, a domain not found in humans but common in many pathogenic bacteria, making it a potential target for antimicrobial development. We have determined the crystal structure of the apo AgrA LytTR domain and screened a library of 500 fragment compounds to find inhibitors of AgrA DNA binding activity. Using nuclear magnetic resonance, the binding site for five compounds has been mapped to a common locus at the C-terminal end of the LytTR domain, a site known to be important for DNA binding activity. Three of these compounds inhibit AgrA DNA binding. These results provide the first evidence that LytTR domains can be targeted by small organic compounds.
Keywords	DNA ; Staphylococcus aureus ; bacteria ; binding sites ; crystal structure ; hemolysins ; humans ; hydrophobicity ; loci ; nuclear magnetic resonance spectroscopy ; organic compounds ; quorum sensing ; transcription factors ; virulence
Language	English
Dates of publication	2012-1218
Size	p. 10035-10043.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021%2Fbi3011785
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: H-NS forms a superhelical protein scaffold for DNA condensation.

Arold, Stefan T / Leonard, Paul G / Parkinson, Gary N / Ladbury, John E

Proceedings of the National Academy of Sciences of the United States of America

2010 Volume 107, Issue 36, Page(s) 15728–15732

Abstract: The histone-like nucleoid structuring (H-NS) protein plays a fundamental role in DNA condensation and is a key regulator of enterobacterial gene expression in response to changes in osmolarity, pH, and temperature. The protein is capable of high-order ... ...

Abstract	The histone-like nucleoid structuring (H-NS) protein plays a fundamental role in DNA condensation and is a key regulator of enterobacterial gene expression in response to changes in osmolarity, pH, and temperature. The protein is capable of high-order self-association via interactions of its oligomerization domain. Using crystallography, we have solved the structure of this complete domain in an oligomerized state. The observed superhelical structure establishes a mechanism for the self-association of H-NS via both an N-terminal antiparallel coiled-coil and a second, hitherto unidentified, helix-turn-helix dimerization interface at the C-terminal end of the oligomerization domain. The helical scaffold suggests the formation of a H-NS:plectonemic DNA nucleoprotein complex that is capable of explaining published biophysical and functional data, and establishes a unifying structural basis for coordinating the DNA packaging and transcription repression functions of H-NS.
MeSH term(s)	Amino Acid Sequence ; Bacterial Proteins/chemistry ; Biopolymers/chemistry ; DNA/chemistry ; DNA-Binding Proteins/chemistry ; Models, Molecular ; Molecular Sequence Data ; Sequence Homology, Amino Acid ; Temperature
Chemical Substances	Bacterial Proteins ; Biopolymers ; DNA-Binding Proteins ; H-NS protein, bacteria ; DNA (9007-49-2)
Language	English
Publishing date	2010-08-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1006966107
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Article: Potent and selective inhibition of SH3 domains with dirhodium metalloinhibitors.

Vohidov, Farrukh / Knudsen, Sarah E / Leonard, Paul G / Ohata, Jun / Wheadon, Michael J / Popp, Brian V / Ladbury, John E / Ball, Zachary T

Chemical science

2015 Volume 6, Issue 8, Page(s) 4778–4783

Abstract: Src-family kinases (SFKs) play important roles in human biology and are key drug targets as well. However, achieving selective inhibition of individual Src-family kinases is challenging due to the high similarity within the protein family. We describe ... ...

Abstract	Src-family kinases (SFKs) play important roles in human biology and are key drug targets as well. However, achieving selective inhibition of individual Src-family kinases is challenging due to the high similarity within the protein family. We describe rhodium(ii) conjugates that deliver both potent and selective inhibition of Src-family SH3 domains. Rhodium(ii) conjugates offer dramatic affinity enhancements due to interactions with specific and unique Lewis-basic histidine residues near the SH3 binding interface, allowing predictable, structure-guided inhibition of SH3 targets that are recalcitrant to traditional inhibitors. In one example, a simple metallopeptide binds the Lyn SH3 domain with 6 nM affinity and exhibits functional activation of Lyn kinase under biologically relevant concentrations (EC
Language	English
Publishing date	2015-06-03
Publishing country	England
Document type	Journal Article
ZDB-ID	2559110-1
ISSN	2041-6539 ; 2041-6520
ISSN (online)	2041-6539
ISSN	2041-6520
DOI	10.1039/c5sc01602a
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