Article
Cell Biology
Joshua D. Frenster, Hediye Erdjument-Bromage, Gabriele Stephan, Niklas Ravn-Boess, Shuai Wang, Wenke Liu, Devin Bready, Jordan Wilcox, Bjorn Kieslich, Manuel Jankovic, Caroline Wilde, Susanne Horn, Norbert Strater, Ines Liebscher, Torsten Schoneberg, David Fenyo, Thomas A. Neubert, Dimitris G. Placantonakis
Summary: This study identifies PTK7 as an extracellular binding partner of GPR133 in glioblastoma, and shows that PTK7 enhances GPR133 signaling by binding to the N-terminal fragment of GPR133. This interaction is potentially relevant to the pathogenesis of glioblastoma.
Review
Chemistry, Multidisciplinary
Keith M. Olson, John R. Traynor, Andrew Alt
Summary: Allosteric modulators (AMs) of G-protein coupled receptors (GPCRs) present desirable drug targets due to their potential to produce fewer on-target side effects and improved selectivity compared to orthosteric drugs. Peptides and proteins, deriving from endogenous protein-protein interactions, intramolecular receptor contacts, endogenous peptides, and exogenous libraries, serve as underappreciated sources for identifying AM leads, offering advantages such as high affinity and bioactivity along with disadvantages like poor metabolic stability. Peptidomimetics combine the advantages of both peptides and small molecules, mimicking peptide chemical features responsible for bioactivity while enhancing druggability.
FRONTIERS IN CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Yousuke Takaoka, Kaho Suzuki, Akira Nozawa, Hirotaka Takahashi, Tatsuya Sawasaki, Minoru Ueda
Summary: This study investigated the protein-protein interactions between MYC3 and MED25 in the JA-Ile signaling pathway. The research revealed that a specific binding domain of MED25 (CMIDM) is crucial for the activation of the JA-Ile signaling pathway. Additionally, quantitative analysis showed that the binding affinity order is JAZ(Jas) < MED25(CMIDM) < JAZ(CMID), indicating a mechanism for activation and negative feedback regulation in jasmonate signaling.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Michael Ippolito, Francesco De Pascali, Nathan Hopfinger, Konstantin E. Komolov, Daniela Laurinavichyute, Poli Adi Narayana Reddy, Leon A. Sakkal, Kyle Z. Rajkowski, Ajay P. Nayak, Justin Lee, Jordan Lee, Gaoyuan Cao, Preston S. Donover, Melvin Reichman, Steven S. An, Joseph M. Salvino, Raymond B. Penn, Roger S. Armen, Charles P. Scott, Jeffrey L. Benovic
Summary: A negative allosteric modulator, DFPQ, was found to selectively inhibit beta-arrestin recruitment to beta(2)AR without affecting its coupling to Gs. This may provide a strategy to improve the functional consequences of beta(2)AR activation.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Chemistry, Medicinal
Heqi Sun, Jianmin Wang, Hongyan Wu, Shenggeng Lin, Junwei Chen, Jinghua Wei, Shuai Lv, Yi Xiong, Dong-Qing Wei
Summary: This study proposes a deep learning framework called MultiPPIMI for predicting the interaction between PPI targets and modulators. Experimental results show that MultiPPIMI performs well in predicting both cold-start scenarios and random-split scenarios, and can assist in screening inhibitors for Keap1/Nrf2 PPI interactions.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Biochemistry & Molecular Biology
Junghyun L. Suh, Daniel Bsteh, Bryce Hart, Yibo Si, Tyler M. Weaver, Carina Pribitzer, Roy Lau, Shivani Soni, Heather Ogana, Justin M. Rectenwald, Jacqueline L. Norris, Stephanie H. Cholensky, Cari Sagum, Jessica D. Umana, Dongxu Li, Brian Hardy, Mark T. Bedford, Shannon M. Mumenthaler, Heinz-Josef Lenz, Yong-Mi Kim, Gang Greg Wang, Ken H. Pearce, Lindsey James, Dmitri B. Kireev, Catherine A. Musselman, Stephen Frye, Oliver Bell
Summary: CBX proteins are cell-type-specific paralogous chromobox proteins that repress developmental genes. We have identified a potent positive allosteric modulator (PAM), UNC7040, for CBX8, which disrupts its binding to H3K27me3 and enhances interactions with nucleic acids. Treatment with UNC7040 efficiently and selectively removes CBX8-containing PRC1 from chromatin, resulting in gene desilencing and reduced proliferation in cancer cells.
CELL CHEMICAL BIOLOGY
(2022)
Article
Cell Biology
Mengrong Li, Yiqiong Bao, Ran Xu, Miaomiao Li, Lili Xi, Jingjing Guo
Summary: The identification and development of non-peptide allosteric modulators for PTH1R have gained attention. It has been found that a negative allosteric modulator (NAM) inhibits the activation of PTH1R, but the mechanism is unclear. Molecular dynamics simulations and analytical approaches reveal that NAM destabilizes the PTH1R-PTH-spep/qpep complexes, weakens PTH/peps-PTH1R binding, and reduces intra- and inter-molecular couplings in PTH1R. Compared with positive allosteric effects induced by extracellular Ca2+, the negative allosteric regulator significantly reduces the correlation between PTH and G-protein binding sites. These findings contribute to the development of new therapeutics for diseases caused by PTH1R abnormal activation.
Article
Neurosciences
Alessandra Porcu, Rafaela Mostallino, Valeria Serra, Miriam Melis, Valeria Sogos, Sarah Beggiato, Luca Ferraro, Fabrizio Manetti, Beatrice Gianibbi, Bernhard Bettler, Federico Corelli, Claudia Mugnaini, M. Paola Castelli
Summary: This study characterized the negative allosteric modulator COR758 for GABA(B) receptors, showing its potential as a therapeutic candidate by inhibiting G protein signaling. COR758 may serve as a scaffold for developing additional NAMs for therapeutic intervention by interacting with an allosteric binding site of GABA(B) receptors.
Article
Chemistry, Multidisciplinary
Julie M. Garlick, Steven M. Sturlis, Paul A. Bruno, Joel A. Yates, Amanda L. Peiffer, Yejun Liu, Laura Goo, LiWei Bao, Samantha N. De Salle, Giselle Tamayo-Castillo, Charles L. Brooks, Sofia D. Merajver, Anna K. Mapp
Summary: Inhibitors of transcriptional protein-protein interactions have high value for both tools and therapeutic applications. This study demonstrates that norstictic acid, a depsidone natural product, blocks Med25-transcriptional activator PPIs through an alternative binding site, providing opportunities for inhibitor discovery in challenging proteins with structurally dynamic loops.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Chemistry, Medicinal
Sumanta Garai, Luciana M. Leo, Anna-Maria Szczesniak, Dow P. Hurst, Peter C. Schaffer, Ayat Zagzoog, Tallan Black, Jeffrey R. Deschamps, Elke Miess, Stefan Schulz, David R. Janero, Alex Straiker, Roger G. Pertwee, Mary E. Abood, Melanie E. M. Kelly, Patricia H. Reggio, Robert B. Laprairie, Ganesh A. Thakur
Summary: By introducing a methyl group at the a-position of the nitro group, the greater potency and efficacy of the 2-phenylindole-based cannabinoid type-1 receptor (CB1R) agonist-positive allosteric modulator was achieved, offering safer therapeutic candidates for glaucoma and potentially other diseases. The diastereoselective CB1R-allosteric modulator interaction was demonstrated for the first time, with one enantiomer showing improved potency and the other biased towards specific signaling pathways. Exploiting G-protein biased CB1R-allosteric modulation shows promise for developing more effective and targeted treatments.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Plant Sciences
Qiang Guo, Yanjun Jing, Yuan Gao, Yitong Liu, Xiaofeng Fang, Rongcheng Lin
Summary: Light signals are perceived by photoreceptors, triggering a developmental transition in dark-germinated seedlings. This process is regulated by Phytochrome-interacting factors (PIFs). In this study, it is shown that histone acetylation is involved in the regulation of phytochrome-PIFs signaling in Arabidopsis. The interaction between histone deacetylase HDA19 and PIF1/PIF3, as well as the Mediator subunit MED25, leads to transcriptional repression through reduction in histone acetylation and chromatin accessibility. Additionally, MED25 forms liquid-like condensates and its puncta increase in darkness, potentially explaining the distinct transcriptional activity of PIF proteins.
Article
Multidisciplinary Sciences
Yuki Toyama, Lewis E. Kay
Summary: Developments in solution NMR spectroscopy have significantly impacted the ability to address biological questions, especially in studying molecular machines critical for cellular homeostasis. NMR plays a key role in elucidating the structural dynamics of important molecules, highlighting intersubunit allosteric communication in homo-oligomers. Through focused experimental studies on individual subunits and the preparation of asymmetric molecules, intersubunit allostery can be directly observed in high-molecular-weight protein systems, showcasing the unique contributions of solution NMR spectroscopy in studying complex biomolecules and emphasizing the synergy between NMR and other atomic resolution biophysical methods.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Medicine, Research & Experimental
Seungkirl Ahn, Harm Maarsingh, Julia K. L. Walker, Samuel Liu, Akhil Hegde, Hyeje C. Sumajit, Alem W. Kahsai, Robert J. Lefkowitz
Summary: This article investigates the potential of β2AR-selective positive allosteric modulators (PAMs) in the treatment of asthma and other obstructive respiratory diseases. The results demonstrate that these PAMs can enhance the binding and downstream signaling of β2-agonists to β2ARs in guinea pigs and humans, thereby promoting bronchodilation and protection.
JOURNAL OF CLINICAL INVESTIGATION
(2023)
Article
Pharmacology & Pharmacy
Jialu Wang, Biswaranjan Pani, Ilhan Gokhan, Xinyu Xiong, Alem W. Kahsai, Haoran Jiang, Seungkirl Ahn, Robert J. Lefkowitz, Howard A. Rockman
Summary: The study demonstrates that Cmpd-6 is a selective beta-arrestin-biased allosteric modulator of beta(1)ARs, enhancing the cardioprotective effect of carvedilol by increasing its binding affinity and cellular signaling, indicating its potential therapeutic application in treating cardiac disease.
MOLECULAR PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Zongju Yang, Baiqiang Yan, Huixue Dong, Guanhua He, Yun Zhou, Jiaqiang Sun
Summary: The study identified a new BZR1-interacting protein, BIC1, which positively regulates BR signaling and acts as a transcriptional coactivator. BIC1 cooperates with PIF4 to activate downstream gene expression, and interacts with BZR1 to regulate common target genes. These findings provide mechanistic insights into BR signaling integration in plants.
Article
Chemistry, Medicinal
Dmitry Borkin, Szymon Klossowski, Jonathan Pollock, Hongzhi Miao, Brian M. Linhares, Katarzyna Kempinska, Zhuang Jin, Trupta Purohit, Bo Wen, Miao He, Duxin Sun, Tomasz Cierpicki, Jolanta Grembecka
JOURNAL OF MEDICINAL CHEMISTRY
(2018)
Article
Chemistry, Medicinal
Huimin Cheng, Brian M. Linhares, Wenbo Yu, Mariano G. Cardenas, Yong Ai, Wenjuan Jiang, Alyssa Winkler, Sandra Cohen, Ari Melnick, Alexander MacKerell, Tomasz Cierpicki, Fengtian Xue
JOURNAL OF MEDICINAL CHEMISTRY
(2018)
Article
Biology
Daniel A. Keedy, Zachary B. Hill, Justin T. Biel, Emily Kang, T. Justin Rettenmaier, Jose Brandao-Neto, Nicholas M. Pearce, Frank von Delft, James A. Wells, James S. Fraser
Article
Biochemistry & Molecular Biology
Hyo Je Cho, Hao Li, Brian M. Linhares, EunGi Kim, Juliano Ndoj, Hongzhi Miao, Jolanta Grembecka, Tomasz Cierpicki
ACS CHEMICAL BIOLOGY
(2018)
Article
Medicine, Research & Experimental
Szymon Klossowski, Hongzhi Miao, Katarzyna Kempinska, Tao Wu, Trupta Purohit, EunGi Kim, Brian M. Linhares, Dong Chen, Gloria Jih, Eric Perkey, Huang Huang, Miao He, Bo Wen, Yi Wang, Ke Yu, Stanley Chun-Wei Lee, Gwenn Danet-Desnoyers, Winifred Trotman, Malathi Kandarpa, Anitria Cotton, Omar Abdel-Wahab, Hongwei Lei, Yali Dou, Monica Guzman, Luke Peterson, Tanja Gruber, Sarah Choi, Duxin Sun, Pingda Ren, Lian-Sheng Li, Yi Liu, Francis Burrows, Ivan Maillard, Tomasz Cierpicki, Jolanta Grembecka
JOURNAL OF CLINICAL INVESTIGATION
(2020)
Review
Chemistry, Medicinal
Brian M. Linhares, Jolanta Grembecka, Tomasz Cierpicki
FUTURE MEDICINAL CHEMISTRY
(2020)
Article
Multidisciplinary Sciences
Matthew J. Henley, Brian M. Linhares, Brittany S. Morgan, Tomasz Cierpicki, Carol A. Fierke, Anna K. Mapp
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2020)
Article
Chemistry, Medicinal
Paulina Fortuna, Brian M. Linhares, Trupta Purohit, Jonathan Pollock, Tomasz Cierpicki, Jolanta Grembecka, Lukasz Berlicki
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2020)
Review
Biotechnology & Applied Microbiology
Matthew J. Henley, Angela N. Koehler
Summary: Transcription factors play important roles in various diseases and recent advancements in chemical biology have provided new possibilities for targeting TFs with small molecules. However, challenges remain, such as addressing structural disorder and finding appropriate targeting strategies.
NATURE REVIEWS DRUG DISCOVERY
(2021)
Article
Chemistry, Multidisciplinary
Stephen T. Joy, Matthew J. Henley, Samantha N. De Salle, Matthew S. Beyersdorf, Isaac W. Vock, Allison J. L. Huldin, Anna K. Mapp
Summary: MybLL-tide is a picomolar dual-site inhibitor of the Myb-CBP/p300 KIX interaction, showing high affinity and selectivity, effectively inhibiting key genes in AML cells.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Chemistry, Organic
Erik S. Goebel, Matthew J. Turcotte, Madeleine J. Henley, Victor G. Young Jr, George Barany
Summary: Two new compounds, 1,1,1-tri(thioacetyl)ethane and 1,1di(thioacetyl)ethene, were synthesized by reacting acetyl methoxy(thiocarbonyl) sulfide with potassium methyl xanthate. The mechanisms involved in these reactions were elucidated, which suggested novel synthetic routes to these compounds. The further transformations of these compounds demonstrated their potential synthetic utility.
JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Meghan E. Breen, Stephen T. Joy, Omari J. Baruti, Matthew S. Beyersdorf, Madeleine J. Henley, Samantha N. De Salle, Peter D. Ycas, Ayza Croskey, Tomasz Cierpicki, William C. K. Pomerantz, Anna K. Mapp
Summary: Natural product garcinolic acid blocks CBP/p300 KIX PPI network by strong interaction with a non-canonical binding site, inhibiting KIX-dependent transcription in leukemia. It selectively engages CBP/p300 KIX domain, disrupting its protein-protein interactions and downregulating essential transcriptional circuits for cMyb-dependent leukemias.
Article
Biochemistry & Molecular Biology
Dymytrii Listunov, Brian M. Linhares, EunGi Kim, Alyssa Winkler, Miranda L. Simes, Sidney Weaver, Hyo Je Cho, Alexandrea Rizo, Sergey Zolov, Venkateshwar G. Keshamouni, Jolanta Grembecka, Tomasz Cierpicki
Summary: The development of GAS41 YEATS inhibitors that block its interaction with acetylated histones has been reported, showing inhibition of NSCLC cell proliferation. This work demonstrates that disrupting GAS41 protein-protein interactions may represent an attractive approach to target lung cancer cells.
CELL CHEMICAL BIOLOGY
(2021)