Article
Chemistry, Multidisciplinary
Huixia Lu, Jordi Marti
Summary: This study proposes a computational framework to accurately assess the conformational variants of a target protein using all-atom Molecular Dynamics and Metadynamics simulations. The research focuses on the G12D mutated GTP bound oncogenic KRas-4B protein and reveals the influence of GTP-binding on the protein's stabilization and potential for opening druggable pockets. The findings provide new opportunities for designing efficient drugs.
Article
Chemistry, Multidisciplinary
Gyula Palfy, Dora K. Menyhard, Hanna Akontz-Kiss, Istvan Vida, Gyula Batta, Orsolya Toke, Andras Perczel
Summary: NMR relaxation techniques and molecular dynamics simulations were used to investigate the slow dynamics in K-Ras. A two-state conformational exchange on the ms timescale was observed in both GDP- and GTP-bound K-Ras. Furthermore, a low-populated higher energy state in GDP-loaded K-Ras was identified, which is involved in the interaction with nucleotide exchange factors and subsequent reactivation.
CHEMISTRY-A EUROPEAN JOURNAL
(2022)
Article
Chemistry, Multidisciplinary
Zhongtang Yu, Xiaoqiang He, Ruiliu Wang, Xinxin Xu, Zhang Zhang, Ke Ding, Zhi-Min Zhang, Yi Tan, Zhengqiu Li
Summary: Due to their unique pharmaceutical properties, targeted covalent inhibitors (TCIs) have emerged as a powerful method for cancer treatment. The K-Ras mutant, which is prevalent in multiple cancers, has been confirmed as a crucial drug target. However, no covalent inhibitors targeting K-Ras(G12D) have been developed yet. We present the first compound capable of engaging both K-Ras(G12D) and K-Ras(G12C) mutants, offering a novel pathway for the development of dual covalent inhibitors.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Multidisciplinary Sciences
Dongsung Kim, Lorenz Herdeis, Dorothea Rudolph, Yulei Zhao, Jark Boettcher, Alberto Vides, Carlos I. I. Ayala-Santos, Yasin Pourfarjam, Antonio Cuevas-Navarro, Jenny Y. Xue, Andreas Mantoulidis, Joachim Broeker, Tobias Wunberg, Otmar Schaaf, Johannes Popow, Bernhard Wolkerstorfer, Katrin Gabriele Kropatsch, Rui Qu, Elisa de Stanchina, Ben Sang, Chuanchuan Li, Darryl B. B. McConnell, Norbert Kraut, Piro Lito
Summary: This study reports the discovery of a non-covalent inhibitor that selectively binds to the inactive state of KRAS while sparing other RAS isoforms. The inhibitor blocks nucleotide exchange and inhibits the activation of wild-type and various KRAS mutants. It shows promising therapeutic potential for KRAS-driven cancers.
Article
Cell Biology
Imran Khan, Akiko Koide, Mariyam Zuberi, Gayatri Ketavarapu, Eric Denbaum, Kai Wen Teng, J. Matthew Rhett, Russell Spencer-Smith, G. Aaron Hobbs, Ernest Ramsay Camp, Shohei Koide, John P. O'Bryan
Summary: This study discovered a compound that selectively binds to the nucleotide-free state of RAS and inhibits the signaling and transforming activity of certain RAS mutants with fast exchange rates. In cell experiments and animal models, this compound exhibited the ability to reduce tumor formation in cancer cells.
Article
Biology
S. Udhaya Kumar, C. George Priya Doss
Summary: The study identified compounds with significant inhibitory functions against K-Ras G12C and G12D mutants, which efficiently bind to mutant K-Ras with a novel binding mechanism similar to sotorasib. Simulation studies showed that the binding of these compounds stabilizes K-Ras in different ways, providing potential drug candidates for targeted therapy.
COMPUTERS IN BIOLOGY AND MEDICINE
(2021)
Article
Chemistry, Multidisciplinary
Ki-Young Lee, Masahiro Enomoto, Teklab Gebregiworgis, Genevieve M. C. Gasmi-Seabrook, Mitsuhiko Ikura, Christopher B. Marshall
Summary: The study found that KRAS forms dimers and multimers (nanoclusters) on the plasma membrane to drive cell signaling and proliferation. The G12D mutation enhances nanoclustering of KRAS. Through investigating the structure of KRAS on the membrane, it was revealed that the G12D mutant self-associates through an asymmetric 'alpha-beta' interface.
Article
Biochemistry & Molecular Biology
Shimaa Salamh, Abdallah Sayyed-Ahmad
Summary: Mutations of Ras proteins are major contributors to cancer, and the redox signaling plays a critical role in controlling the activity of Ras through the oxidation of C118. This study investigated the structural and conformational effects of C118 oxidation on the oncogenic mutant KRas(G12D) using molecular dynamics simulations and Markov state models. The oxidized variant KRas(G12D/C118SOH) was found to be more dynamic than the unoxidized counterpart, affecting the nucleotide-binding site and switch regions as well as the conformational equilibrium between active and inactive states. These findings provide insights for future drug development targeting KRAS-related anticancer treatments.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Oncology
Mehreen Ghufran, Haider Ali Khan, Mehran Ullah, Sabreen Ghufran, Muhammad Ayaz, Muhammad Siddiq, Syed Shams ul Hassan, Simona Bungau
Summary: The study aimed to create peptides that inhibit K-Ras G12V using computer-aided drug design methods. The results showed that the selected peptides had stronger interactions with K-Ras and could block its activation, demonstrating the potential to inhibit K-Ras and slow cancer growth.
Article
Multidisciplinary Sciences
Yan Xu, Houshun Fang, Yao Chen, Yabin Tang, Huiying Sun, Ziqing Kong, Fan Yang, Renate Kirschner-Schwabe, Liang Zhu, Alex Toker, Ning Xiao, Bin-Bing S. Zhou, Hui Li
Summary: Mutations in RAS pathway genes are common in acute lymphoblastic leukemia (ALL). The KRAS-G12D mutation increases cell proliferation in vitro but impairs growth in mice. This mutation rewires methionine and arginine metabolism, promoting catabolism of these amino acids to support the synthesis of polyamines and proline. Inhibiting polyamine biosynthesis selectively kills KRAS-G12D B-ALL cells. Additionally, inhibiting the AKT/mTOR signaling pathway restores amino acid metabolism and promotes the growth of KRAS-G12D cells in vivo.
Article
Multidisciplinary Sciences
Quentin Van Thillo, Jolien De Bie, Janith A. Seneviratne, Sofie Demeyer, Sofia Omari, Anushree Balachandran, Vicki Zhai, Wai L. Tam, Bram Sweron, Ellen Geerdens, Olga Gielen, Sarah Provost, Heidi Segers, Nancy Boeckx, Glenn M. Marshall, Belamy B. Cheung, Kiyotaka Isobe, Itaru Kato, Junko Takita, Timothy G. Amos, Ira W. Deveson, Hannah McCalmont, Richard B. Lock, Ethan P. Oxley, Maximilian M. Garwood, Ross A. Dickins, Anne Uyttebroeck, Daniel R. Carter, Jan Cools, Charles E. de Bock
Summary: The SPI1 fusion genes and NRAS mutations are commonly found in T-ALL, and their combination is essential for driving leukemia in a murine model. The oncogenic activity of SPI1 fusion is dependent on beta-catenin, and targeting the TCF/beta-catenin interaction could be a potential therapeutic strategy.
NATURE COMMUNICATIONS
(2021)
Article
Medicine, Research & Experimental
Linlin Yang, Zhefeng Li, Daniel W. Binzel, Peixuan Guo, Terence M. Williams
Summary: This study suggests that nanoparticles targeting mutant KRAS can effectively suppress cancer cell proliferation and migration, and enhance sensitivity to chemoradiotherapy in lung cancer. These findings highlight the potential of this nanoparticle-based platform as a novel treatment strategy for KRAS-driven human cancers.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2023)
Article
Biochemistry & Molecular Biology
Udhaya S. Kumar, R. Bithia, Thirumal D. Kumar, C. George Priya Doss, Hatem Zayed
Summary: This study investigates the effects of oncogenic mutations at position 12 of K-Ras on protein stability and GTP binding. The G12A and G12V mutants exhibited the strongest binding efficiency. Molecular dynamics simulations showed that the G12A mutant had a more stable structure compared to the wildtype. This study contributes to understanding the molecular mechanisms involved in cancer development and provides a platform for targeted cancer therapies.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2022)
Article
Biochemistry & Molecular Biology
Nada Ragab, Julia Bauer, Dominik S. Botermann, Anja Uhmann, Heidi Hahn
Summary: The study shows that oncNRAS mutations accelerate tumor growth in immature ERMS precursors within a specific time window, shortening ERMS-free survival and increasing ERMS incidence. However, it does not alter tumor differentiation and is not involved in tumor initiation. This indicates that oncNRAS-associated processes differ in dependency on their occurrence during tumor development.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Cell Biology
Jeeho Kim, Young Jin Jeon, Sung-Chul Lim, Joohyun Ryu, Jung-Hee Lee, In-Youb Chang, Ho Jin You
Summary: Ephexin1 is highly expressed in patient tissues of colorectal cancer (CRC) and lung cancer (LC), and plays a critical role in promoting tumorigenesis through the Ras-mediated signaling pathway. Phosphorylated Ephexin1 at Ser16 and Ser18 (pSer16/18) may serve as an effective therapeutic target for CRC and LC as it interacts with oncogenic K-Ras to promote downstream MAPK signaling.
CELL DEATH & DISEASE
(2021)
Article
Oncology
Riyue Bao, Anita Ng, Mark Sasaki, Myvizhi Esai Selvan, Alyna Katti, Hyesan Lee, Lei Huang, Andrew D. Skol, Cinzia Lavarino, Hector Salvador, Robert J. Klein, Zeynep H. Gumus, Jaume Mora, Kenan Onel
Summary: Whole-exome sequencing in a Spanish and Catalan family revealed a rare germline variant in ERBB2 associated with familial cancer risk. Functional assays showed that this variant activates ERBB2 signaling, increasing the risk of cancer.
CANCER PREVENTION RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Burak Erman
Summary: The coarse-grained Gaussian network model (GNM) only considers the alpha carbons of the folded protein, limiting its applicability to mutation and ligand binding studies. By including all atom pairs within the coordination shell, the Kirchoff adjacency matrix of the protein is modified, allowing for a more comprehensive understanding of the effects of mutation and ligand binding on residue fluctuations and correlations.
Article
Oncology
Semanti Mukherjee, Chaitanya Bandlamudi, Matthew D. Hellmann, Yelena Kemel, Esther Drill, Hira Rizvi, Kaitlyn Tkachuk, Aliya Khurram, Michael F. Walsh, Marjorie G. Zauderer, Diana Mandelker, Sabine Topka, Ahmet Zehir, Preethi Srinivasan, Myvizhi Esai Selvan, Maria I. Carlo, Karen A. Cadoo, Alicia Latham, Jada G. Hamilton, Ying L. Liu, Steven M. Lipkin, Sami Belhadj, Gareth L. Bond, Zeynep H. Gumus, Robert J. Klein, Marc Ladanyi, David B. Solit, Mark E. Robson, David R. Jones, Mark G. Kris, Joseph Vijai, Zsofia K. Stadler, Christopher I. Amos, Barry S. Taylor, Michael F. Berger, Charles M. Rudin, Kenneth Offit
Summary: This study found that germline pathogenic/likely pathogenic variants (PV) in lung cancer predisposing genes are associated with a higher risk of developing lung cancer. These variants, particularly in DNA damage repair (DDR) pathway genes, are closely related to biallelic inactivation in tumors. It also revealed that patients with germline PV in lung cancer predisposing genes tend to be diagnosed at a younger age, and high-risk patients are more likely to carry germline PV.
CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION
(2022)
Article
Oncology
Xiaoyu Song, Meng Ru, Zoe Steinsnyder, Kaitlyn Tkachuk, Ryan P. Kopp, John Sullivan, Zeynep H. Gumus, Kenneth Offit, Vijai Joseph, Robert J. Klein
Summary: This study found that SNP rs2702185 at the SMG7 locus is associated with time from biochemical recurrence to prostate cancer death, and its LD partner rs10737246 is predicted to be functional. These results suggest that future association studies of prostate cancer survival should consider various intervals over the course of disease.
CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION
(2022)
Article
Chemistry, Physical
Aysima Hacisuleyman, Burak Erman
Summary: Based on Schreiber's work on transfer entropy, a molecular theory of nonlinear information transfer between residue pairs in proteins is developed, and the importance of harmonic and nonlinear contributions to information transfer in protein allosteric activity is discussed.
JOURNAL OF CHEMICAL PHYSICS
(2022)
Review
Oncology
Robert J. Klein, Zeynep H. Gumus
Summary: In order to achieve the goals of precision medicine in complex diseases, discriminative clinical risk models are necessary. Polygenic risk scores (PRSs) have been proposed as one approach with potential clinical utility in cancer. However, the utility of PRSs depends on their actionability, discriminative power, and comparison with existing practice.
TRANSLATIONAL LUNG CANCER RESEARCH
(2022)
Article
Biochemical Research Methods
Turkan Haliloglu, Aysima Hacisuleyman, Burak Erman
Summary: In this article, a computational model is presented to predict the paths of maximum information transfer between active and allosteric sites in proteins by using mutual information as the measure. The model is tested on six widely studied cases and the results correlate well with experimental data. The model provides crucial information for understanding and controlling protein functionality.
Article
Biology
Yingjun Liu, Assunta Senatore, Silvia Sorce, Mario Nuvolone, Jingjing Guo, Zeynep H. Gumus, Adriano Aguzzi
Summary: Cultured brain slices from mice upregulate senescence-associated genes and reproduce transcriptional characteristics of aged brains. Prions accelerate brain aging. This study establishes an innovative model system for studying brain aging.
COMMUNICATIONS BIOLOGY
(2022)
Correction
Biology
Yingjun Liu, Assunta Senatore, Silvia Sorce, Mario Nuvolone, Jingjing Guo, Zeynep H. Gumus, Adriano Aguzzi
COMMUNICATIONS BIOLOGY
(2022)
Review
Oncology
Qian Wang, Zeynep H. Gumus, Cristina Colarossi, Lorenzo Memeo, Xintong Wang, Chung Yin Kong, Paolo Boffetta
Summary: This article reviews research on the epidemiology, risk factors, genetic susceptibility, molecular pathology, and early detection of small cell lung cancer (SCLC). It summarizes the changing incidences of SCLC globally and in the United States, discusses the established risk factor of tobacco smoking, and highlights the importance of tobacco control. The review also explores genetic susceptibility, molecular pathology, and the limited utility of low-dose computed tomography screening in SCLC, as well as promising blood-based molecular biomarkers for early detection.
JOURNAL OF THORACIC ONCOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Burak Erman
Summary: This paper proposes a computational framework for evaluating the dependence of mutations on mutual information, and investigates specific patterns and changes in allosteric pathways caused by mutations. By calculating the mutual information between residues using both Gaussian and nonlinear terms, it is found that the Gaussian term provides sufficiently accurate representation of mutual information.
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
(2023)
Article
Oncology
Myvizhi Esai Selvan, Kenan Onel, Sacha Gnjatic, Robert J. Klein, Zeynep H. Gumus
Summary: Recent studies have shown that rare, deleterious variants (RDVs) in specific genes play a critical role in heritable cancer risk. By analyzing whole-exome sequencing data of 20,789 participants, we identified associations between cancer risk and RDVs in DNA repair, cancer predisposition, and somatic cancer drivers. Moreover, we found that personal RDV load in these gene-sets is associated with increased risk, earlier onset, increased M1 macrophages in tumor, and increased tumor mutational burden in specific cancers. These findings can be used to identify high-risk individuals and improve prognosis through increased surveillance, earlier screening, and targeted treatments.
NPJ PRECISION ONCOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Aysima Hacisuleyman, Burak Erman
Summary: This paper aims to understand the binding strategies of a nanobody-protein pair by studying known complexes. Rigid body protein-ligand docking programs produce several complexes, called decoys, which are good candidates with high scores of shape complementarity, electrostatic interactions, desolvation, buried surface area, and Lennard-Jones potentials. Based on the analysis of 36 crystal structures and evidence from existing literature, a set of principles for the design of nanobodies is proposed.
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
(2023)
Article
Chemistry, Medicinal
Ozge Soylu-Eter, Zekiye Seyma Sevincli, Betul Ersoy, Bahar Hasanusta, Ugur Gatfar, Nathan A. Lack, Burak Erman, Ahmet Gul, Hakan S. Orer, Nilgun Karali
Summary: This study aimed to develop drugs with anti-interleukin-1 activity. Through evaluation and screening of compounds, as well as in vitro studies and molecular modeling, it was found that compounds 78 and 81 had the strongest IL-1 receptor inhibitory effects and the most favorable drug-like properties.
ARCHIV DER PHARMAZIE
(2023)
Review
Biology
Walter Wolfsberger, Karishma Chhugani, Khrystyna Shchubelka, Alina Frolova, Yuriy Salyha, Oksana Zlenko, Mykhailo Arych, Dmytro Dziuba, Andrii Parkhomenko, Volodymyr Smolanka, Zeynep H. Guemues, Efe Sezgin, Alondra Diaz-Lameiro, Viktor R. Toth, Megi Maci, Eric Bortz, Fyodor Kondrashov, Patricia M. Morton, Pawel P. Labaj, Veronika Romero, Jakub Hlavka, Serghei Mangul, Taras K. Oleksyk
Summary: Conflicts and natural disasters not only cause destruction to lives, but also have a significant negative impact on the scientific advancements of the affected countries. These events result in infrastructure collapse, destruction of educational and research institutions, and hinder the progress of scientists. In our interconnected world, conflicts and disasters have far-reaching effects on the global community.