Article
Multidisciplinary Sciences
Dhanir Tailor, Fernando Jose Garcia-Marques, Abel Bermudez, Sharon J. Pitteri, Sanjay V. Malhotra
Summary: GBP1 plays an important role in ovarian cancer cells, and its inhibition can limit the clonogenic potential of cancer cells. In addition, GBP1 overexpression promotes tumor progression and decreases median survival, while GBP1 inhibition delays tumor progression and increases median survival. Furthermore, GBP1 interacts with multiple members of the proteasome, affecting the sensitivity of OC cells to paclitaxel treatment by controlling proteasomal activity.
Article
Multidisciplinary Sciences
Jianping Li, Ampon Sae Her, Nathaniel J. Traaseth
Summary: EmrE is a multidrug efflux pump in Escherichia coli that transports drugs as a homodimer using energy from the proton motive force. Research suggests that the two Glu14 residues in the dimer have independent pKa values and are not electrostatically coupled, supporting a transport pathway with well-defined protonation states in each monomer of the dimer. The findings also propose a model, hop-free exchange, for how exchangers with conformation-dependent pKa values reduce proton leakage, relevant to the SMR family and transporters with inverted repeat domains.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biochemistry & Molecular Biology
Sergey A. Vishnivetskiy, Liana D. Weinstein, Chen Zheng, Eugenia V. Gurevich, Vsevolod V. Gurevich
Summary: Arresin-1 shows selectivity for light-activated phosphorylated rhodopsin, and this selectivity is mediated by two structural elements in the molecule. In the crystal structure, there are some residues close to rhodopsin that do not belong to the selectivity mechanism. Mutations in these residues enhance binding to unphosphorylated rhodopsin and increase its selectivity for phosphorylated rhodopsin. This challenges the current model of arrestin-receptor interactions.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Catia A. Bonito, Ricardo J. Ferreira, Maria-Jose U. Ferreira, Jean-Pierre Gillet, M. Natalia D. S. Cordeiro, Daniel J. V. A. dos Santos
Summary: In this study, the impact of four P-gp mutations on drug-binding and efflux-related signal-transmission mechanism was evaluated. The repacking of the transmembrane helices induced by mutations and ligands indicates P-gp's sensitivity to perturbations in the transmembrane region. Changes in drug-binding were observed as a consequence of transmembrane helices repacking, but were not always correlated with alterations in ligand binding mode and affinity. The changes in drug efflux are mostly related to changes in drug specificity rather than effects on signal-transmission mechanism.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Chemistry, Medicinal
Aleksandra V. Sagaidak, Svetlana V. Vorona, Daria S. Novikova, Tatyana A. Grigoreva, Vyacheslav G. Tribulovich
Summary: The modulation of efflux transporters of the ABC family, especially P-glycoprotein, is crucial in overcoming transporter-mediated multidrug resistance in cancer therapy. A universal target for rational drug design is the nucleotide binding domain, which can be inhibited by ATP mimetics to suppress drug efflux. These compounds show promising potential as therapeutic efflux modulators, as they enhance the antitumor efficacy without inducing transporter overexpression.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Medicine, Research & Experimental
Yu Feng, Jingcao Huang, Fangfang Wang, Zhimei Lin, Hongmei Luo, Qian Li, Xin Wang, Xiang Liu, Xinyu Zhai, Qianwen Gao, Lingfeng Li, Yue Zhang, Jingjing Wen, Li Zhang, Ting Niu, Yuhuan Zheng
Summary: The study revealed that high MCCA expression in patients with MM led to improved overall survival. Knockdown of MCCA in MM cells resulted in increased survival rates after treatment with different anti-MM drugs. Mechanistic studies showed dysfunctional mitochondria in MCCA-KD cells and protein-protein interactions between MCCA and Bad. Additionally, MCCA was found to contribute to multidrug resistance in various human cancers.
Article
Biochemistry & Molecular Biology
James I. Mitchell-White, Thomas Stockner, Nicholas Holliday, Stephen J. Briddon, Ian D. Kerr
Summary: Members of the mammalian G subfamily of ATP-binding cassette transporters exhibit significant differences in substrate specificity, with ABCG2 playing a crucial role in multidrug resistance due to its wide substrate specificity. Analysis of conservation differences between members in a multiple sequence alignment of ABCG sequences from mammals reveals possible explanations for functional differences. Mapping sets of residues onto the 3D structure of ABCG2 illustrates a network of residues that may confer additional conformational flexibility, allowing for transport of a wider array of substrates.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Tamas Pivarcsik, Orsolya Domotor, Janos P. Meszaros, Nora May, Gabriella Spengler, Oszkar Csuvik, Istvan Szatmari, Eva A. Enyedy
Summary: The study revealed that two novel 8-hydroxyquinoline-D-proline and homo-proline hybrids exhibit good solution stability and cytotoxicity in various cell lines, showing potential anti-tumor activities.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Ahmed R. Sofy, Noha K. El-Dougdoug, Ehab E. Refaey, Rehab A. Dawoud, Ahmed A. Hmed
Summary: This research describes a novel phage, KPP-5, capable of lysing multidrug-resistant K. pneumoniae isolated from food samples in Egypt. The phage exhibited strong lytic activity, short latent period, and high stability, with no virulence or drug resistance genes detected in its genome, suggesting it could be safely utilized as a phage biocontrol agent.
Article
Biochemistry & Molecular Biology
Jie Wang, Xu Li, Fang-Fang Wang, Meng-Ting Cheng, Yao-Xu Mao, Shu-Cheng Fang, Liang Wang, Cong-Zhao Zhou, Wen-Tao Hou, Yuxing Chen
Summary: The human ABC transporter ABCC3 is responsible for transporting a wide range of substances, including endogenous metabolites and drugs. Its dysfunction is associated with various diseases such as intrahepatic cholestasis of pregnancy. The study provides structural insights into the substrate binding pocket of ABCC3, which can hold conjugated hormones in an asymmetric pattern and may be used for designing inhibitors.
Article
Chemistry, Medicinal
Arun K. Ghosh, Satish Kovela, Ashish Sharma, Dana Shahabi, Ajay K. Ghosh, Denver R. Hopkins, Monika Yadav, Megan E. Johnson, Johnson Agniswamy, Yuan-Fang Wang, Shin-Ichiro Hattori, Nobuyo Higashi-Kuwata, Manabu Aoki, Masayuki Amano, Irene T. Weber, Hiroaki Mitsuya
Summary: This study reports the design, synthesis, X-ray structural analysis, and biological evaluation of highly potent HIV-1 protease inhibitors. The inhibitors combine a novel cyclohexane-fused tricyclic bis-tetrahydrofuran as P2 ligands with various P1 and P2' ligands. The inhibitor with difluoromethylphenyl P1 ligand and cyclopropylaminobenzothiazole P2' ligand demonstrates the most potent antiviral activity, including against highly multidrug-resistant HIV-1 variants. Two high-resolution X-ray structures of inhibitor-bound HIV-1 protease provide molecular insight.
Article
Oncology
Hadiar Rahman, Mark J. J. Ware, Andaleeb Sajid, Sabrina Lusvarghi, Stewart R. R. Durell, Suresh V. V. Ambudkar
Summary: This study investigates the conformational changes of P-glycoprotein (P-gp) during drug transport and reveals the critical role of TMHs 4 and 10 in substrate transport.
Article
Chemistry, Multidisciplinary
Karan Kapoor, Sundar Thangapandian, Emad Tajkhorshid
Summary: Proteins can sample a broad landscape as they undergo conformational transition between different functional states. Considering the different conformational states of a protein is central for a successful drug-design strategy. In this study, a novel docking protocol, termed extended-ensemble docking, is introduced for proteins that undergo large-scale conformational changes. The results show the importance of incorporating the global conformational flexibility of proteins in future drug-discovery endeavors.
Article
Chemistry, Medicinal
Conghui Wang, Meng Gao, Shuqi Liu, Zongji Zou, Ruiyin Ren, Chen Zhang, Hao Xie, Jingxian Sun, Yupeng Qi, Qi Qu, Zhihua Song, Gangqiang Yang, Hongbo Wang
Summary: The study demonstrated that pyxinol derivatives can serve as modulators against Pgp-mediated cancer multidrug resistance. The synthesized pyxinol derivatives linked to amino acid residues effectively reversed MDR in KBV cells, with compound 3c showing the best activity.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Aqsa Shaheen, Anam Tariq, Fouzia Ismat, Hammad Naveed, Rita De Zorzi, Mazhar Iqbal, Paola Storici, Osman Mirza, Thomas Walz, Moazur Rahman
Summary: This study used the AlphaFold model to identify residues of the multidrug efflux transporter styMdtM, and confirmed their importance through mutagenesis experiments. The findings revealed that mutation of specific residues can result in loss of transport function, while mutation of peripheral residues has no effect on structure or function. Additionally, crystallization studies provided valuable data on the protein's structure.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Biochemistry & Molecular Biology
M. Fahad Miah, Gwenaelle Conseil, Susan P. C. Cole
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2016)
Article
Pharmacology & Pharmacy
Mayukh Banerjee, Vanessa Marensi, Gwenaelle Conseil, X. Chris Le, Susan P. C. Cole, Elaine M. Leslie
BIOCHEMICAL PHARMACOLOGY
(2016)
Review
Oncology
Yinghong Huang, Susan P. C. Cole, Tiange Cai, Yu Cai
Article
Pharmacology & Pharmacy
Kevin E. Weigl, Gwenaelle Conseil, Alice J. Rothnie, May Arama, Yossi Tsfadia, Susan P. C. Cole
MOLECULAR PHARMACOLOGY
(2018)
Review
Pharmacology & Pharmacy
Susan P. C. Cole
ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 54
(2014)
Article
Pharmacology & Pharmacy
Leanna Cheung, Claudia L. Flemming, Fujiko Watt, Nanako Masada, Denise M. T. Yu, Tony Huynh, Gwenaelle Conseil, Amanda Tivnan, Alexander Polinsky, Andrei V. Gudkov, Marcia A. Munoz, Anasuya Vishvanath, Dermot M. F. Cooper, Michelle J. Henderson, Susan P. C. Cole, Jamie I. Fletcher, Michelle Haber, Murray D. Norris
BIOCHEMICAL PHARMACOLOGY
(2014)
Article
Biochemistry & Molecular Biology
Surtaj H. Iram, Susan P. C. Cole
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
(2014)
Review
Biochemistry & Molecular Biology
Susan P. C. Cole
JOURNAL OF BIOLOGICAL CHEMISTRY
(2014)
Article
Urology & Nephrology
Joonhee Park, Jin-Oh Kwak, Brigitte Riederer, Ursula Seidler, Susan P. C. Cole, Hwa Jeong Lee, Min Goo Lee
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
(2014)
Article
Cell Biology
Daqing Jin, Terri T. Ni, Jianjian Sun, Haiyan Wan, Jeffrey D. Amack, Guangju Yu, Jonathan Fleming, Chin Chiang, Wenyan Li, Anna Papierniak, Satish Cheepala, Gwenaelle Conseil, Susan P. C. Cole, Bin Zhou, Iain A. Drummond, John D. Schuetz, Jarema Malicki, Tao P. Zhong
NATURE CELL BIOLOGY
(2014)
Article
Biochemistry & Molecular Biology
Gwenaelle Conseil, May Arama-Chayoth, Yossi Tsfadia, Susan P. C. Cole
Article
Pharmacology & Pharmacy
Christine C. Gana, Kimberley M. Hanssen, Denise M. T. Yu, Claudia L. Flemming, Madeleine S. Wheatley, Gwenaelle Conseil, Susan P. C. Cole, Murray D. Norris, Michelle Haber, Jamie I. Fletcher
BIOCHEMICAL PHARMACOLOGY
(2019)
Article
Pharmacology & Pharmacy
Caley B. Shukalek, Diane P. Swanlund, Rodney K. Rousseau, Kevin E. Weigl, Vanessa Marensi, Susan P. C. Cole, Elaine M. Leslie
MOLECULAR PHARMACOLOGY
(2016)
Article
Pharmacology & Pharmacy
Mark A. Csandl, Gwenaelle Conseil, Susan P. C. Cole
DRUG METABOLISM AND DISPOSITION
(2016)
Article
Pharmacology & Pharmacy
Gwenaelle Conseil, Susan P. C. Cole
DRUG METABOLISM AND DISPOSITION
(2013)