Article
Endocrinology & Metabolism
Shuai Huang, Junmei Wang, Li Zhang, Shasha Tian, Yao Wang, Xian Shao, Saijun Zhou, Pei Yu
Summary: This study demonstrates the important role of RasGRP4 in the progression of diabetic kidney disease, suggesting that it promotes inflammatory injury through regulating the interaction between peripheral blood mononuclear cells and glomerular endothelial cells.
METABOLISM-CLINICAL AND EXPERIMENTAL
(2022)
Review
Chemistry, Medicinal
Severin K. Thompson, Andreas Buckl, Alexander G. Dossetter, Ed Griffen, Adrian Gill
Summary: SOS1 plays a crucial role in RAS signaling pathways, and small-molecule inhibitors and activators targeting the SOS1:RAS interaction show potential therapeutic effects. Research on SOS1 inhibitors has increased in recent years, and the interest in this area is expected to remain strong in the future.
EXPERT OPINION ON THERAPEUTIC PATENTS
(2021)
Article
Biochemistry & Molecular Biology
Minh Huynh, Derek Parsonage, Tom E. Forshaw, Venkat R. Chirasani, G. Aaron Hobbs, Hanzhi Wu, Jingyun Lee, Cristina M. Furdui, Leslie B. Poole, Sharon L. Campbell
Summary: The recent development of mutant-selective inhibitors for the oncogenic KRAS(G12C) allele has generated excitement. These inhibitors covalently engage the mutant C12 thiol, locking the KRAS(G12C) protein in an inactive state. However, there are still mechanistic questions regarding the reactivity of this thiol.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Guangmei Luo, Bingrui Wang, Qiangqiang Hou, Xiaoxing Wu
Summary: Son of sevenless homologue 1 (SOS1) protein is expressed in all cells and plays a crucial role in the RAS signaling pathway by interacting with RAS and activating downstream signaling pathways. Targeting SOS1 provides a novel approach for treating RAS-driven cancers.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Biochemistry & Molecular Biology
Dirk Kessler, Daniel Gerlach, Norbert Kraut, Darryl B. McConnell
Summary: Son of Sevenless (SOS) is a guanine nucleotide exchange factor that plays a key role in activating the important cell signaling switch KRAS. Inhibition of SOS1 with potent inhibitors like BI-3406 has shown promising antiproliferative effects against various oncogenic KRAS mutants. The first SOS1 inhibitor has entered clinical trials for KRAS-mutated cancers, highlighting the potential therapeutic significance of targeting this pathway.
CURRENT OPINION IN CHEMICAL BIOLOGY
(2021)
Editorial Material
Cell Biology
Bor Luen Tang
Summary: This article provides an editorial overview of the papers collected in this Special Issue on the Regulation and Function of Small GTPases 2.0.
Article
Biochemistry & Molecular Biology
Tanushree Tunstall, Jody Phelan, Charlotte Eccleston, Taane G. Clark, Nicholas Furnham
Summary: Resistance to drugs used to treat tuberculosis disease remains a public health burden, with missense mutations in Mycobacterium tuberculosis bacteria affecting the stability and ligand affinity of the pncA protein. Multiple mutations at active site residues highlight mutational diversity due to selection pressures. Weak associations were found between genomic measures and biophysical effects of mutations, but statistically significant differences in structural features were observed for mutations associated with PZA resistance. Additionally, a distinct protein stability profile was seen for mutations in M. tuberculosis lineage 1 compared to modern lineages.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Minh Huynh, G. Aaron Hobbs, Antje Schaefer, Mariaelena Pierobon, Leiah M. Carey, J. Nathaniel Diehl, Jonathan M. DeLiberty, Ryan D. Thurman, Adelaide R. Cooke, Craig M. Goodwin, Joshua H. Cook, Lin Lin, Andrew M. Waters, Naim U. Rashid, Emanuel F. Petricoin, Sharon L. Campbell, Kevin M. Haigis, Diane M. Simeone, Costas A. Lyssiotis, Adrienne D. Cox, Channing J. Der
Summary: Missense mutations at the three hotspots in RAS-Gly(12), Gly(13), and Gln(61) show differential distribution among the three RAS isoforms. KRAS(Q61) mutants exhibit various changes in morphology, growth transformation, effector signaling, and metabolism. Differences in biochemical, structural, and biological properties may explain the frequency variations. Targeting KRAS(Q61) mutant-specific signaling and cellular output may be a potential therapeutic strategy.
Article
Biochemistry & Molecular Biology
Christian W. Johnson, Hyuk-Soo Seo, Elizabeth M. Terrell, Moon-Hee Yang, Fenneke KleinJan, Teklab Gebregiworgis, Genevieve M. C. Gasmi-Seabrook, Ezekiel A. Geffken, Jimit Lakhani, Kijun Song, Puspalata Bashyal, Olesja Popow, Joao A. Paulo, Andrea Liu, Carla Mattos, Christopher B. Marshall, Mitsuhiko Ikura, Deborah K. Morrison, Sirano Dhe-Paganon, Kevin M. Haigis
Summary: A conserved GTPase cycle is a unifying feature of the RAS superfamily, in which the proteins transition between active and inactive states. Autophosphorylation of some GTPases serves as an intrinsic regulatory mechanism that affects nucleotide hydrolysis and exchange, thereby altering the signaling functions. The autophosphorylation promotes nucleotide exchange by opening the active site and extracting the stabilizing Mg2+, and leads to altered effector interactions and active site dynamics.
Article
Biochemistry & Molecular Biology
Angelo Felline, Francesco Raimondi, Sara Gentile, Francesca Fanelli
Summary: Ras GTPases function as molecular switches, cycling between OFF and ON states depending on the bound nucleotide. The Rab GTPase Sec4p plays regulatory roles in intracellular vesicle trafficking. This study integrated structural information with molecular dynamics simulations to investigate the dynamics of Sec2p and Sec4p, as well as the chain of structural deformations leading to GEF-assisted activation of the Rab GTPase.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2022)
Article
Chemistry, Physical
Simge Senyuz, Hyunbum Jang, Ruth Nussinov, Ozlem Keskin, Attila Gursoy
Summary: Rac1 is a key GTPase protein involved in cellular biology and diseases, with mutations like P29S and A159V associated with melanoma and head and neck cancer, respectively. These mutations activate Rac1 through different mechanisms, affecting the conformation of Switch I in GTP-bound states.
JOURNAL OF PHYSICAL CHEMISTRY B
(2021)
Review
Immunology
Xuehua Xu, Tian Jin
Summary: Chemotaxis is essential in leukocyte recruitment during inflammation. Adaptation is a strategy for cells to respond to chemoattractant gradients. Ras activation is the first step in GPCR signaling pathways, and Ras inhibitors regulate cell sensitivity.
FRONTIERS IN IMMUNOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Na Li, Chen-Fu Liu, Wen Zhang, Guo-Wu Rao
Summary: This article reviews the development of small molecule covalent inhibitors targeting K-Ras(G12C), highlighting and analyzing the structural evolution and optimization process of each series of inhibitors and the previous inhibitor design methods and strategies, in order to provide inspiration and help to subsequent researchers.
CURRENT MEDICINAL CHEMISTRY
(2023)
Review
Oncology
Christian Johnson, Deborah L. Burkhart, Kevin M. Haigis
Summary: Members of the RAS proto-oncogene family, particularly KRAS, have been extensively studied for their role in cancer initiation. Despite this, therapeutic strategies targeting these proteins are only just starting to be developed. This study highlights the distinct properties of different KRAS alleles and discusses their implications for potential therapeutic avenues.
Article
Biochemistry & Molecular Biology
Sachio Suzuki, Akinobu Nakamura, Yuka Hatano, Masaru Yoshikawa, Tatsuyuki Yoshii, Shunsuke Sawada, Kyoko Atsuta-Tsunoda, Kazuhiro Aoki, Shinya Tsukiji
Summary: This article reports a universal PM-targeting tag for protein translocation using loop-engineered eDHFR tag and m(D)cTMP pair. The method can be widely applied for conditional PM recruitment and activation of tag-fused signaling proteins with different fusion configurations, as well as reversibly and repeatedly controlling protein localization to generate synthetic signal oscillations.
CELL CHEMICAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Amanda L. Loshbaugh, Tanja Kortemme
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
(2020)
Article
Biology
Samuel Thompson, Yang Zhang, Christine Ingle, Kimberly A. Reynolds, Tanja Kortemme
Article
Multidisciplinary Sciences
Xingjie Pan, Michael C. Thompson, Yang Zhang, Lin Liu, James S. Fraser, Mark J. S. Kelly, Tanja Kortemme
Article
Biochemical Research Methods
James E. Lucas, Tanja Kortemme
PLOS COMPUTATIONAL BIOLOGY
(2020)
Review
Endocrinology & Metabolism
Ben F. Brian, Tanya S. Freedman
Summary: Effective regulation of immune-cell activation is crucial to minimize tissue damage caused by unrestrained inflammation and immune response. Lyn kinase plays a critical role in regulating immunoreceptor signaling, and defects in Lyn signaling can lead to autoimmune disease.
Review
Immunology
Joseph Greene, Ben F. Brian Iv, S. Erandika Senevirathne, Tanya Freedman
Summary: Myeloid cells play a crucial role in surveilling the body for infection and damage, regulating tissue homeostasis, and initiating immune responses. Their activation is tightly regulated to balance immune protection and tissue preservation.
CURRENT OPINION IN IMMUNOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Robert G. Alberstein, Amy B. Guo, Tanja Kortemme
Summary: Protein switches play essential roles in biological processes and are challenging to design computationally due to their complex requirements. Inspired by natural protein switches, various methods have been developed to overcome this challenge and explore new ways to design purpose-built switches and signaling systems for cellular engineering.
CURRENT OPINION IN STRUCTURAL BIOLOGY
(2022)
Article
Engineering, Electrical & Electronic
Simon Kretschmer, Tanja Kortemme
Summary: Synthetic biology approaches challenges in healthcare and sustainability with an engineering perspective. Designing biomolecular circuits with programmable input-output behaviors is crucial. However, the limited repertoire of natural sensors and difficulties in interfacing with engineered circuits restrict the sensing capabilities. Computational protein design offers the potential to engineer modular and tunable sensors that can be tailored for different applications. This review focuses on recent approaches using the Rosetta software suite to design protein-based sensors for small-molecule inputs and discusses mechanisms for coupling ligand inputs to functional outputs.
PROCEEDINGS OF THE IEEE
(2022)
Article
Multidisciplinary Sciences
Ben F. Brian, Frances Sjaastad, Tanya S. Freedman
Summary: Csk is a negative regulator of Src-family kinases (SFKs) through phosphorylation and binding with phosphatases. It can homodimerize and its interactions are important for its regulatory function. Investigating Csk homodimerization and phosphatase interactions may reveal new aspects of SFK regulation.
SCIENTIFIC REPORTS
(2022)
Article
Multidisciplinary Sciences
Ben F. Brian, Monica L. Sauer, Joseph T. Greene, S. Erandika Senevirathne, Anders J. Lindstedt, Olivia L. Funk, Brian L. Ruis, Luis A. Ramirez, Jennifer L. Auger, Whitney L. Swanson, Myra G. Nunez, Branden S. Moriarity, Clifford A. Lowell, Bryce A. Binstadt, Tanya S. Freedman
Summary: This study reveals the distinct immunological functions of different splice variants of the Lyn kinase in vivo. LynB isoform exerts a dominant immunosuppressive function, while LynA isoform is uniquely required to restrain autoimmunity in female mice. Through gene editing, single-isoform LynA or LynB knockout mouse models were generated, showing isoform-specific and sexually dimorphic regulation of immune cell development and autoimmune diseases.
Article
Biochemistry & Molecular Biology
Christopher J. P. Mathy, Tanja Kortemme
Summary: Allosteric regulation is the action where perturbations outside the active site of a protein affect its function. While studies on the structural mechanisms of allosteric regulation have been extensive, the translational applicability to entire cellular processes and their crosstalk has been lacking, despite the acknowledged importance of allostery in cellular regulation. In this article, an evolutionary model for the widespread occurrence of allosteric regulation in colocalized proteins is revisited, supporting evidence is presented, and emerging advances in mapping allostery in cellular networks are discussed.
CURRENT OPINION IN STRUCTURAL BIOLOGY
(2023)
Article
Biochemical Research Methods
Simon Kretschmer, Nicholas Perry, Yang Zhang, Tanja Kortemme
Summary: Protein-based switches that respond to different inputs are crucial in synthetic biology. Multi-input switches that integrate multiple signals for regulating a shared output are of particular interest. The nuclear hormone receptor (NHR) superfamily provides a promising platform for engineering multi-input-controlled responses to approved drugs. By exchanging the ligand binding domain (LBD) of the ecdysone receptor (EcR) with other human NHR-derived LBDs, novel (multi)drug regulation can be achieved. This high-level control validates NHRs as a versatile platform for programming multidrug-controlled responses.
ACS SYNTHETIC BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Christopher J. P. Mathy, Parul Mishra, Julia M. Flynn, Tina Perica, David Mavor, Daniel N. A. Bolon, Tanja Kortemme
Summary: The study reveals that the regulation of GTPase proteins occurs not only at specific positions but also distributed throughout the structure. The discovery of new regulatory sites provides a functional map for exploring and targeting GTPases controlling essential biological processes.
Correction
Multidisciplinary Sciences
Anum Glasgow, Helen T. Hobbs, Zion R. Perry, Malcolm L. Wells, Susan Marqusee, Tanja Kortemme
NATURE COMMUNICATIONS
(2023)
Meeting Abstract
Immunology
Ben F. Brian, Myra Nunez, Tanya S. Freedman
JOURNAL OF IMMUNOLOGY
(2020)