Article
Chemistry, Multidisciplinary
Till Rudack, Christian Teuber, Marvin Scherlo, Joern Gueldenhaupt, Jonas Schartner, Mathias Luebben, Johann Klare, Klaus Gerwert, Carsten Koetting
Summary: Studying the Ras dimer structure has shown that inhibiting the dimerization of oncogenic Ras can suppress cancer cell growth. By incorporating unnatural amino acids into Ras and utilizing labeling methods, the accuracy of the dimer structure model can be validated.
Article
Multidisciplinary Sciences
Katarzyna Z. Haza, Heather L. Martin, Ajinkya Rao, Amy L. Turner, Sophie E. Saunders, Britta Petersen, Christian Tiede, Kevin Tipping, Anna A. Tang, Modupe Ajayi, Thomas Taylor, Maia Harvey, Keri M. Fishwick, Thomas L. Adams, Thembaninkosi G. Gaule, Chi H. Trinh, Matthew Johnson, Alexander L. Breeze, Thomas A. Edwards, Michael J. McPherson, Darren C. Tomlinson
Summary: This study identified two RAS-binding Affimer proteins, K3 and K6, which inhibit RAS signaling by binding to different regions on the RAS surface, demonstrating the potential use of Affimers as tools to identify new binding pockets and pharmacophores.
NATURE COMMUNICATIONS
(2021)
Article
Biology
Fa-An Chao, Albert H. Chan, Srisathiyanarayanan Dharmaiah, Charles D. Schwieters, Timothy H. Tran, Troy Taylor, Nitya Ramakrishnan, Dominic Esposito, Dwight V. Nissley, Frank McCormick, Dhirendra K. Simanshu, Gabriel Cornilescu
Summary: Structural analysis of GMPPNP-bound KRAS(G13D) reveals an intermediate state with a new pocket, providing an opportunity for developing targeted therapies against KRAS(G13D)-driven cancers. Dynamics of RAS, including distal regions, is important for understanding its interactions with effectors and designing inhibitors. Methyl relaxation dispersion experiments show synchronized conformational dynamics in active KRAS(G13D), suggesting an exchange between two states. Residual dipolar couplings and crystal structures confirm the presence of an intermediate state distinct from known conformations.
COMMUNICATIONS BIOLOGY
(2023)
Article
Biochemical Research Methods
Jonathan P. Hannan, G. Hayden Swisher, Justin G. Martyr, Nicholas J. Cordaro, Annette H. Erbse, Joseph J. Falke
Summary: The study introduces a new method for analyzing the bound nucleotide composition of G proteins loaded with activating or inactivating nucleotides, which is highly reproducible. The method has been successfully applied to HRas samples and mutants, resolving the fractional on- and off-state populations, and proposing a new hypothesis for the molecular disease mechanism of Ras mutations at the E63 and Y64 positions.
ANALYTICAL BIOCHEMISTRY
(2021)
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
Biophysics
Van A. Ngo, Angel E. Garcia
Summary: Molecular dynamics simulations revealed that KRas dimers exhibit multiple conformations, with some involving HVR and α(2) helix, potentially mediating dimerization. Certain dimer configurations may contribute to the recruitment of cytosolic Raf kinases, while a variant of the dimer interface similar to HRas was identified.
BIOPHYSICAL JOURNAL
(2022)
Article
Chemistry, Physical
Meryem Eren, Nurcan Tuncbag, Hyunbum Jang, Ruth Nussinov, Attila Gursoy, Ozlem Keskin
Summary: The study reveals that KRas4B exhibits partner-specific dynamics when interacting with different proteins, shedding light on the intricate protein-protein interactions involved in cellular signaling.
JOURNAL OF PHYSICAL CHEMISTRY B
(2021)
Article
Chemistry, Medicinal
Jianzhong Chen, Shaolong Zhang, Wei Wang, Laixue Pang, Qinggang Zhang, Xinguo Liu
Summary: The mutations G12V and D33E in K-Ras significantly alter the flexibility of SW1 and SW2, as well as affecting their correlated motions relative to the P-loop and each other, leading to a tuning of K-Ras activity. Analysis of free energy landscapes also reveals the conformational disorders in SW1 and SW2, which may impact the binding of guanine nucleotide exchange factors or effectors to K-Ras, with instability in hydrogen-bonding interactions being a key factor.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2021)
Article
Biophysics
Alicia Y. Volmar, Hugo Guterres, Hao Zhou, Derion Reid, Spiro Pavlopoulos, Lee Makowski, Carla Mattos
Summary: HRas, KRas, and NRas are structurally similar GTPases with isoform-specific residues that affect different functional regions around the active site. HRas, KRas, and NRas each have unique mechanisms through which their specific residues influence the stability of the nucleotide-binding pocket and the conformation of switch regions. The study revealed that KRas is the most flexible of the three isoforms, with isoform-specific residues leading to the greatest fluctuations in switch regions.
BIOPHYSICAL JOURNAL
(2022)
Article
Chemistry, Physical
Juan Zeng, Jian Chen, Fei Xia, Qiang Cui, Xianming Deng, Xin Xu
Summary: This study analyzes the conformational landscape of KRas during the GTP hydrolysis cycle and reveals the existence of multiple stable substates in different chemical states. These substates may interact with different binding partners and provide insights for inhibition strategies targeting KRas.
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
(2022)
Article
Chemistry, Physical
Hui Wang, Dan Liu, Yongkui Yu, Mengqi Fang, Xue Gu, Dong Long
Summary: Recent advances in direct inhibition of Ras have utilized the protein's dynamic nature to target therapeutically vulnerable conformers. Researchers have explored the effects of oncogenic mutations and activation states on Ras conformational dynamics, identifying critical conformational reorganizations that affect drug accessibility. These findings offer insights for developing allele-specific and pan-Ras inhibitors and support the conformational selection scenario for Ras-binder interactions.
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
(2023)
Article
Biochemistry & Molecular Biology
Ruth Nussinov, Hyunbum Jang, Attila Gursoy, Ozlem Keskin, Vadim Gaponenko
Summary: Drug action is related to blocking the mechanism of activation, not to whether the protein is in the active or inactive state.
CELL CHEMICAL BIOLOGY
(2021)
Article
Food Science & Technology
Samo Lesnik, Marko Jukic, Urban Bren
Summary: Rosemary is an important medicinal plant with antioxidative, anti-inflammatory, and anticarcinogenic activities. In this study, molecular dynamics simulations coupled with free-energy calculations were conducted on previously identified ligand-protein complexes to investigate the binding behavior of carnosic acid, carnosol, rosmanol, and rosmarinic acid. The results showed that carnosic acid and rosmanol can bind to HIV-1 protease, while carnosol may bind to K-RAS oncogene protein. However, rosmarinic acid exhibited weak binding with factor X. The study also highlighted the role of water-mediated hydrogen-bond networks in stabilizing the binding conformation of these polyphenols and explaining their promiscuous nature.
Review
Biochemistry & Molecular Biology
Guowei Yin, Jing Huang, Johnny Petela, Hongmei Jiang, Yuetong Zhang, Siqi Gong, Jiaxin Wu, Bei Liu, Jianyou Shi, Yijun Gao
Summary: Small GTPases are essential in regulating cellular functions and therapeutic targets for various diseases. Traditionally considered undruggable, breakthrough strategies have recently enabled the targeting of mutated oncogenes such as KRAS. Despite progress, many small GTPases and hotspot mutations remain elusive, and resistance to current inhibitors poses challenges.
SIGNAL TRANSDUCTION AND TARGETED THERAPY
(2023)
Article
Biophysics
Chunhua Yuan, Alexandar L. Hansen, Lei Bruschweiler-Li, Rafael Bruschweiler
Summary: This study reports the sequence-specific resonance assignments of wild-type and oncogenic G12C and G12D mutants of K-Ras protein in the GTP-complexed active forms, providing a basis for comprehensive functional dynamics study.
BIOMOLECULAR NMR ASSIGNMENTS
(2023)