Article
Biochemistry & Molecular Biology
Masashi Yukawa, Mitsuki Ohishi, Yusuke Yamada, Takashi Toda
Summary: In the absence of kinesin-5, deletion of the dri1 gene in fission yeast can rescue temperature sensitivity caused by kinesin-5 mutants. This deletion also significantly reduces the levels of kinesin-14/Klp2 on the spindles in the kinesin-5 mutants. The RNA-binding motifs of Dri1 are essential for its cytoplasmic localization and function.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Medicinal
Ryota Fukai, Naohisa Ogo, Taiki Ichida, Masayoshi Yamane, Jun-ichi Sawada, Nao Miyoshi, Hisashi Murakami, Akira Asai
Summary: The researchers optimized the design of KSP inhibitors through computational modeling and developed a prodrug compound that could be hydrolyzed by GGT to produce an inhibitor with KSP ATPase inhibitory activity and demonstrated higher selectivity toxicity in GGT-expressing cancer cells.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Cell Biology
Dayna L. Mercadante, William A. Aaron, Sarah D. Olson, Amity L. Manning
Summary: During cell division, the centrosome, which is responsible for microtubule organization, plays a crucial role in forming a bipolar spindle. Extra centrosomes can lead to multipolar spindles and result in non-viable cells. In this study, experimental and computational approaches were used to investigate the role of cortical dynein in centrosome clustering. It was found that perturbation of cortical dynein disrupted centrosome clustering and led to the dominance of multipolar spindles. The results highlight the importance of dynamic relocalization of dynein in promoting timely centrosome clustering and bipolar cell division in cells with extra centrosomes.
MOLECULAR BIOLOGY OF THE CELL
(2023)
Review
Medicine, Research & Experimental
Rand Shahin, Salah Aljamal
Summary: Halting the cell cycle in mitosis and interfering with its normal progression is an effective anti-cancer strategy. Traditional anti-cancer drugs directly inhibit microtubules during cell division, but they have serious side effects. On the other hand, KSP inhibitors are receiving attention as less toxic mitotic inhibitors. This review tracks the medicinal chemistry developmental stages of KSP inhibitors and discusses the challenges and future insights in developing active KSP inhibitor drugs for cancer treatment.
Article
Multidisciplinary Sciences
Byron Hunter, Matthieu P. M. H. Benoit, Ana B. Asenjo, Caitlin Doubleday, Daria Trofimova, Corey Frazer, Irsa Shoukat, Hernando Sosa, John S. Allingham
Summary: This study reveals how Kinesin-8 alternates between promotility and pro-microtubule-depolymerization states by regulating its tubulin structure through the loop-2 region. Structural changes induced by curved microtubule ends and straight protofilaments result in different functional outcomes.
NATURE COMMUNICATIONS
(2022)
Article
Biology
Mihaela Jagric, Patrik Risteski, Jelena Martincic, Ana Milas, Iva M. Tolic
Summary: The study revealed that bridging fibers play a crucial role in chromosome alignment by promoting alignment through length-dependent forces. It was found that PRC1-mediated crosslinking of bridging microtubules and recruitment of kinesins to the bridging fiber are essential mechanisms for chromosome alignment.
Article
Biochemistry & Molecular Biology
Islam Md Alrazi, Kei Sadakane, Shinsaku Maruta
Summary: A novel photoresponsive inhibitor composed of spiropyran and azobenzene derivatives has been synthesized to control Eg5 function with precise multistage inhibitory activity. The inhibitor exhibited three isomerization states, each correlating with changes in ATPase and motor activities, providing precise control of Eg5 function at three different levels using light irradiation.
JOURNAL OF BIOCHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Islam Md Alrazi, Kei Sadakane, Shinsaku Maruta
Summary: The study synthesized a novel photoresponsive inhibitor, SPSAB, to control Eg5 function with multistage inhibitory activity and formation of different isomerization states. SPSAB exhibited three isomerization states under visible light, ultraviolet, and in the dark, enabling precise control of Eg5 function with light irradiation. The results showed that the SP-trans isomer of SPSAB had potent inhibitory activity, while MC-trans and MC-cis displayed less inhibitory activity, highlighting the potential of the photochromic inhibitor for precise control of Eg5 function at different levels.
JOURNAL OF BIOCHEMISTRY
(2021)
Article
Chemistry, Physical
Navjeet Ahalawat, Jagannath Mondal
Summary: Computer simulation approaches have greatly advanced in biomolecular recognition processes, particularly through unbiased simulation and Markov state modeling methods. Enhanced sampling approaches are crucial in accelerating simulations of ligand recognition processes, but key issues such as force fields and sampling bottlenecks still need to be addressed to achieve quantitative reconstruction of experimental measurements. Adopting multiscale approaches and coarse-grained simulations may be a possible way forward for efficient elucidation of ligand binding kinetics.
JOURNAL OF PHYSICAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Analytical
Rebekka Van Hoof, Michal Szymonik, Stefanos K. Nomidis, Karen Hollanders, An Jacobs, Inge Nelissen, Patrick Wagner, Jef Hooyberghs
Summary: This paper discusses the physicochemical aspects of hybridization-based detection of low-abundance mutations, demonstrating improvements in DNA mutation sensing through the introduction of specific probes and depletion effects, with potential clinical applications in liquid biopsy contexts.
SENSORS AND ACTUATORS B-CHEMICAL
(2022)
Article
Chemistry, Physical
Vinay V. Nair, Guowei Yin, Jerry Zhang, John F. Hancock, Sharon L. Campbell, Alemayehu A. Gorfe
Summary: KRAS, as a 21 kDa guanine nucleotide-binding protein, serves as a molecular switch in regulating cellular growth. Post-translational modification by monoubiquitination at specific sites like K104 and K147 impacts the structure and function of KRAS, but the detailed mechanism is not fully understood. This study uses molecular dynamics simulations and NMR spectroscopy data to show that ubiquitination at these sites modulates conformational fluctuations in KRAS, shedding light on potential therapeutic targeting strategies.
JOURNAL OF PHYSICAL CHEMISTRY B
(2021)
Article
Biology
Duangjai Todsaporn, Panupong Mahalapbutr, Rungtiva P. Poo-arporn, Kiattawee Choowongkomon, Thanyada Rungrotmongkol
Summary: In this study, the effects of EGFR mutations on the susceptibility of different EGFR inhibitors were investigated using comprehensive molecular modeling and in vitro kinase inhibition assays. The results showed that three hot-spot residues were involved in the binding of osimertinib and afatinib to mutated EGFRs, enhancing their inhibitory activity. Furthermore, principal component analysis revealed that the molecular complexation of osimertinib against mutated EGFRs was in a closed conformation, leading to drug resistance.
COMPUTERS IN BIOLOGY AND MEDICINE
(2022)
Article
Oncology
Shanshan Deng, Souvik Banerjee, Hao Chen, Satyanarayana Pochampally, Yuxi Wang, Mi-Kyung Yun, Stephen W. White, Keyur Parmar, Bernd Meibohm, Kelli L. Hartman, Zhongzhi Wu, Duane D. Miller, Wei Li
Summary: This study reports a novel inhibitor, SB226, which shows great promise for cancer therapy. Through extensive preclinical studies and in vitro/in vivo experiments, it was confirmed that SB226 has high affinity for tubulin dimers, exhibits anti-proliferative activities, inhibits tumor growth, induces apoptosis, and shows no obvious toxicity.
Article
Cell Biology
Ian D. Wolff, Jeremy A. Hollis, Sarah M. Wignall
Summary: This study investigates the mechanism of acentrosomal spindle assembly in oocytes, focusing on the role of the kinesin-12 family motor KLP-18. The researchers identify a microtubule binding site on the C-terminal stalk of KLP-18 and demonstrate that its interaction with the adaptor protein MESP-1 activates nonmotor microtubule binding. They also provide evidence that this C-terminal domain is necessary for KLP-18 activity during spindle assembly and continuous maintenance of spindle bipolarity. This study provides new insight into the construction and maintenance of the acentrosomal spindle in oocytes, as well as the mechanism and regulation of kinesin-12.
MOLECULAR BIOLOGY OF THE CELL
(2022)
Article
Biochemistry & Molecular Biology
Kimberly C. Grasty, Claudia Guzik, Elizabeth J. D'Lauro, Shae B. Padrick, Joris Beld, Patrick J. Loll
Summary: The VanRS two-component system controls the resistance of vancomycin-resistant enterococci. The sensor VanS autophosphorylates and transfers the phosphate group to the response regulator VanR, activating it as a transcription factor for resistance gene expression. Crystal structures of the catalytic and ATP-binding domains of VanS proteins reveal the Bergerat fold seen in other histidine kinases. Interestingly, the domains display low affinities for ATP, suggesting a potential regulatory mechanism for resistance phenotype expression.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Review
Chemistry, Medicinal
Robert A. Pearlstein, K. Andrew MacCannell, Gul Erdemli, Sarita Yeola, Gabriel Helmlinger, Qi-Ying Hu, Ramy Farid, William Egan, Steven Whitebread, Clayton Springer, Jeremy Beck, Hao-Ran Wang, Mateusz Maciejewski, Laszlo Urban, Jose S. Duca
CURRENT TOPICS IN MEDICINAL CHEMISTRY
(2016)
Article
Biochemistry & Molecular Biology
Bradley Sherborne, Veerabahu Shanmugasundaram, Alan C. Cheng, Clara D. Christ, Renee L. DesJarlais, Jose S. Duca, Richard A. Lewis, Deborah A. Loughney, Eric S. Manas, Georgia B. McGaughey, Catherine E. Peishoff, Herman van Vlijmen
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
(2016)
Article
Chemistry, Medicinal
B. Barry Toure, John Giraldes, Troy Smith, Elizabeth R. Sprague, Yaping Wang, Simon Mathieu, Zhuoliang Chen, Yuji Mishina, Yun Feng, Yan Yan-Neale, Subarna Shakya, Dongshu Chen, Matthew Meyer, David Puleo, J. Tres Brazell, Christopher Straub, David Sage, Kirk Wright, Yanqiu Yuan, Xin Chen, Jose Duca, Sean Kim, Li Tian, Eric Martin, Kristen Hurov, Wenlin Shao
JOURNAL OF MEDICINAL CHEMISTRY
(2016)
Article
Chemistry, Medicinal
Callum J. Dickson, Viktor Hornak, Camilo Velez-Vega, Daniel J. J. McKay, John Reilly, David A. Sandham, Duncan Shaw, Robin A. Fairhurs, Steven J. Charlton, David A. Sykes, Robert A. Pearlstein, Jose S. Duca
JOURNAL OF MEDICINAL CHEMISTRY
(2016)
Article
Chemistry, Multidisciplinary
Callum J. Dickson, Viktor Hornak, Robert A. Pearlstein, Jose S. Duca
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2017)
Article
Chemistry, Medicinal
Xin Chen, John Giraldes, Elizabeth R. Sprague, Subarna Shakya, Zhuoliang Chen, Yaping Wang, Carol Joud, Simon Mathieu, Christine Hiu-Tung Chen, Christopher Straub, Jose Duca, Kristen Hurov, Yanqiu Yuan, Wenlin Shao, B. Barry Toure
JOURNAL OF MEDICINAL CHEMISTRY
(2017)
Article
Chemistry, Medicinal
Callum J. Dickson, Viktor Hornak, Dallas Bednarczyk, Jose S. Duca
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2019)
Article
Chemistry, Medicinal
Jose Jimenez, Davide Sabbadin, Alberto Cuzzolin, Gerard Martinez-Rosell, Jacob Gora, John Manchester, Jose Duca, Gianni De Fabritiis
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2019)
Article
Biochemistry & Molecular Biology
Keith Jendza, Mitsunori Kato, Michael Salcius, Honnappa Srinivas, Andrea De Erkenez, Anh Nguyen, Doug McLaughlin, Celine Be, Christian Wiesmann, Jason Murphy, Philippe Bolduc, Muneto Mogi, Jose Duca, Abdel Namil, Michael Capparelli, Veronique Darsigny, Erik Meredith, Ritesh Tichkule, Luciana Ferrara, Jessica Heyder, Fang Liu, Patricia A. Horton, Michael J. Romanowski, Markus Schirle, Nello Mainolfi, Karen Anderson, Gregory A. Michaud
NATURE CHEMICAL BIOLOGY
(2019)
Article
Multidisciplinary Sciences
Lieyang Chen, Anthony Cruz, Steven Ramsey, Callum J. Dickson, Jose S. Duca, Viktor Hornak, David R. Koes, Tom Kurtzman
Article
Chemistry, Medicinal
Callum J. Dickson, Camilo Velez-Vega, Jose S. Duca
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2020)
Review
Biotechnology & Applied Microbiology
Petra Schneider, W. Patrick Walters, Alleyn T. Plowright, Norman Sieroka, Jennifer Listgarten, Robert A. Goodnow, Jasmin Fisher, Johanna M. Jansen, Jose S. Duca, Thomas S. Rush, Matthias Zentgraf, John Edward Hill, Elizabeth Krutoholow, Matthias Kohler, Jeff Blaney, Kimito Funatsu, Chris Luebkemann, Gisbert Schneider
NATURE REVIEWS DRUG DISCOVERY
(2020)
Article
Chemistry, Physical
Christos Lamprakis, Ioannis Andreadelis, John Manchester, Camilo Velez-Vega, Jose S. Duca, Zoe Cournia
Summary: The study suggests that Martini 2.2P overestimates the free energy of association for proteins, while Martini 3 performs better in describing the association of membrane proteins. Near-native dimer complexes are identified as minima in the free energy surface, although not always as the lowest minima.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2021)
Article
Chemistry, Multidisciplinary
Anna Pavlova, Diane L. Lynch, Isabella Daidone, Laura Zanetti-Polzi, Micholas Dean Smith, Chris Chipot, Daniel W. Kneller, Andrey Kovalevsky, Leighton Coates, Andrei A. Golosov, Callum J. Dickson, Camilo Velez-Vega, Jose S. Duca, Josh V. Vermaas, Yui Tik Pang, Atanu Acharya, Jerry M. Parks, Jeremy C. Smith, James C. Gumbart
Summary: The main protease of SARS-CoV-2 is a promising target for antiviral therapeutics, crucial in the viral life cycle. The stability of its structure is highly sensitive to the protonation states of key residues, impacting drug design efforts.
Review
Chemistry, Medicinal
Robert A. Pearlstein, Daniel J. J. McKay, Viktor Hornak, Callum Dickson, Andrei Golosov, Tyler Harrison, Camilo Velez-Vega, Jose Duca
CURRENT TOPICS IN MEDICINAL CHEMISTRY
(2017)