Article
Hematology
Mohammad Azhar, Zachary Kincaid, Meenu Kesarwani, Jacob Menke, Joshua Schwieterman, Sekhu Ansari, Angela Reaves, Arhama Ahmed, Rammsha Shehzad, Areeba Khan, Nuha Syed, Noor Amir, Mark Wunderlich, Tahir Latif, William Seibel, Mohammad Azam
Summary: Despite advancements in FLT3 inhibitors, treatment resistance remains common due to acquired mutations and activation of signaling pathways. In this study, pluripotin was identified as a potent inhibitor of FLT3, BCR-ABL, and JAK2, as well as Ras-GAP and ERK1. Structural modeling revealed pluripotin's ability to selectively bind with inactive conformations of these kinases. Pluripotin showed efficacy in suppressing adaptive resistance and demonstrated promising results in inhibiting AML progression in vivo.
Review
Pharmacology & Pharmacy
Yuran Qiu, Yuanhao Wang, Zongtao Chai, Duan Ni, Xinyi Li, Jun Pu, Jie Chen, Jian Zhang, Shaoyong Lu, Chuan Lv, Mingfei Ji
Summary: RAS is a key oncogenic protein, and mutations in it can lead to human cancer. Recent studies have identified several phosphorylation residues in RAS protein that can regulate its activity, providing a new direction for developing anti-RAS drugs. This review summarizes the research advances in RAS phosphorylation and provides insights into therapeutic strategies.
ACTA PHARMACEUTICA SINICA B
(2021)
Article
Multidisciplinary Sciences
Padma Akkapeddi, Takamitsu Hattori, Imran Khan, Eliezra Glasser, Akiko Koide, Gayatri Ketavarapu, Michael Whaby, Mariyam Zuberi, Kai Wen Teng, Julia Lefler, Lorenzo Maso, Injin Bang, Michael C. Ostrowski, John P. O'Bryan, Shohei Koide
Summary: Researchers have developed monobodies, synthetic binding proteins, that selectively bind to KRAS(G12D) and inhibit its signaling and tumorigenesis. These monobodies directly recognize the side chain of KRAS Asp12 using their backbone NH group, similar to small-molecule inhibitors. They also interact with a non-conserved residue, H95, in KRAS, contributing to their high selectivity and mechanism of action.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Chemistry, Multidisciplinary
Yan Xiong, Yue Zhong, Hyerin Yim, Xiaobao Yang, Kwang-Su Park, Ling Xie, Poulikos I. Poulikakos, Xiaoran Han, Yue Xiong, Xian Chen, Jing Liu, Jian Jin
Summary: Proteolysis Targeting Chimeras (PROTACs) are effective for degrading disease-causing proteins. A novel approach called bridged PROTAC has been developed to target undruggable proteins by bringing the protein complex close to an E3 ubiquitin ligase using a small molecule binder of the target protein's binding partner. This approach has led to the discovery of MS28, the first-in-class degrader of cyclin D1, and it shows superior degradation efficiency and proliferation inhibition compared to CDK4/6 inhibitors and degraders. The bridged PROTAC strategy could serve as a generalizable platform for targeting undruggable proteins.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Review
Biochemistry & Molecular Biology
Cristina Olivieri, Caitlin Walker, Manu Veliparambil Subrahmanian, Fernando Porcelli, Susan S. Taylor, David A. Bernlohr, Gianluigi Veglia
Summary: The cAMP-dependent protein kinase A (PKA) is a highly conserved eukaryotic kinase. PKA-C is a bilobal enzyme with a dynamic N-lobe and a more rigid helical C-lobe. It exhibits positive binding cooperativity between nucleotide and substrate. Mutations in PKA-C disrupt the allosteric communication between lobes, leading to a decrease in cooperativity, changes in substrate fidelity, and reduced affinity for protein kinase inhibitor (PKI). This may contribute to dysregulation and disease.
Article
Cell Biology
Amr Kataya, Nitija Gautam, Muhammad Jamshed, Douglas G. Muench, Marcus A. Samuel, Jay J. Thelen, Greg B. Moorhead
Summary: This study identified protein kinases in peroxisomes and investigated their functions and regulation. The findings provide new insights into the regulation of peroxisome functions.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Mirco Dindo, Stefano Pascarelli, Davide Chiasserini, Silvia Grottelli, Claudio Costantini, Gen-Ichiro Uechi, Giorgio Giardina, Paola Laurino, Barbara Cellini
Summary: This study demonstrates how protein evolution balances structural stability and dynamics to maximize protein adaptability and preserve protein fitness, with naturally occurring genetic variations tipping the balance between stability and frustration.
Article
Chemistry, Medicinal
Lovika Mittal, Mitul Srivastava, Anita Kumari, Rajiv K. Tonk, Amit Awasthi, Shailendra Asthana
Summary: The study focuses on the dynamics and plasticity of the PD-1/PD-L1 axis, revealing increased structural stability and coordinated movements in the presence of binding partners. Through computational biophysical approaches, hot-spots essential for arresting the dynamic motions of PD-1 significantly are identified, providing insights for the rational design of therapeutic agents mimicking the mechanism of monoclonal antibodies.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2021)
Article
Biochemistry & Molecular Biology
Igor E. Eliseev, Valeria M. Ukrainskaya, Anna N. Yudenko, Anna D. Mikushina, Stanislav Shmakov, Anastasiya Afremova, Viktoria M. Ekimova, Anna A. Vronskaia, Nickolay A. Knyazev, Olga Shamova
Summary: The novel heavy-chain antibodies developed in this study target the ErbB3 receptor through a unique approach, showing promising potential in overcoming resistance to pharmacological inhibition of EGFR and HER2 receptors in cancer treatment. These antibodies exhibit non-competitive binding to distinct epitopes on the receptor and have demonstrated efficacy in inhibiting proliferation through different mechanisms, paving the way for potential development of new therapeutic strategies for malignant tumors.
Review
Pharmacology & Pharmacy
Yongjian Liu, Hongliu Yang, Yongsheng Fang, Yantao Xing, Xinxin Pang, Yang Li, Yuanyuan Zhang, Yonggang Liu
Summary: Haspin, a nuclear protein kinase, plays a crucial role in cell cycle progression and its overexpression is associated with cancer cell proliferation and apoptosis. Inhibitors targeting Haspin are currently being developed for cancer treatment.
JOURNAL OF PHARMACY AND PHARMACOLOGY
(2023)
Article
Virology
Rajkumar Lalji Sahani, Raquel Diana-Rivero, Sanjeev Kumar V. Vernekar, Lei Wang, Haijuan Du, Huanchun Zhang, Andres Emanuelli Castaner, Mary C. Casey, Karen A. Kirby, Philip R. Tedbury, Jiashu Xie, Stefan G. Sarafianos, Zhengqiang Wang
Summary: Research on multiple PF74 analogs demonstrated that two series of compounds replacing the phenylalanine carboxamide moiety have potential as candidates. Metabolic stability assays also indicated that blocking the C5 position of the indole ring could enhance resistance to oxidative metabolism.
Article
Chemistry, Multidisciplinary
Khoa N. Pham, Ariel Lewis-Ballester, Syun-Ru Yeh
Summary: This study used carbon monoxide as a structural probe to investigate how the functionalities of hIDO1 and hTDO are encoded in their structures. The findings revealed the remarkable conformational plasticity of hIDO1 and the more rigid protein architecture of hTDO, providing new insights into the structure and function relationships of heme-based dioxygenases.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Editorial Material
Hematology
Monika Haemmerle
Summary: This study explores the role of Mnk1 in megakaryocytes and platelets, showing that it regulates protein synthesis and affects megakaryocyte ploidy and platelet production. These findings have clinical implications and contribute to our understanding of platelet function and thrombosis.
Article
Chemistry, Medicinal
Jannis Born, Yoel Shoshan, Tien Huynh, Wendy D. Cornell, Eric J. Martin, Matteo Manica
Summary: Recent research has shown that incorporating active site information improves the accuracy of predicting the binding affinity between kinases and ligands. In this study, we propose and compare multiple definitions of the active site, and provide significant evidence to support the superiority of our novel definition over previous ones, especially in modeling ATP-noncompetitive inhibitors. Additionally, we utilize the discontiguity of the active site sequence to develop novel protein sequence augmentation strategies, which further enhance the predictive performance.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Letter
Chemistry, Medicinal
Jannis Born, Yoel Shoshan, Tien Huynh, Wendy D. Cornell, Eric J. Martin, Matteo Manica
Summary: Recent work suggests that using active site information instead of full protein sequence improves the accuracy of predicting kinase-ligand binding affinity. In this study, we propose and compare multiple definitions of the active site, and find that our novel definition outperforms previous definitions and better models ATP noncompetitive inhibitors. Additionally, by leveraging the discontiguity of the active site sequence, we develop novel protein-sequence augmentation strategies that further enhance performance.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Biochemistry & Molecular Biology
Steven K. Albanese, Daniel L. Parton, Mehtap Isik, Lucelenie Rodriguez-Laureano, Sonya M. Hanson, Julie M. Behr, Scott Gradia, Chris Jeans, Nicholas M. Levinson, Markus A. Seeliger, John D. Chodera
Article
Genetics & Heredity
Jingming Wang, Bryan Chan, Michael Tong, YiTing Paung, Ukhyun Jo, Dwight Martin, Markus Seeliger, John Haley, Hyungjin Kim
Article
Biochemistry & Molecular Biology
Juan Pablo Maianti, Grace A. Tan, Amedeo Vetere, Arnie J. Welsh, Bridget K. Wagner, Markus A. Seeliger, David R. Liu
NATURE CHEMICAL BIOLOGY
(2019)
Article
Cell Biology
Michael J. Grey, Eva Cloots, Mariska S. Simpson, Nicole LeDuc, Yevgeniy Serebrenik, Heidi De Luca, DeLphine De Sutter, Phi Luong, Jay R. Thiagarajah, Adrienne W. Paton, James C. Paton, Markus A. Seeliger, Sven Eyckerman, Sophie Janssens, Wayne Lencer
JOURNAL OF CELL BIOLOGY
(2020)
Article
Biochemistry & Molecular Biology
Linglan Fang, Jessica Vilas-Boas, Sujata Chakraborty, Zachary E. Potter, Ames C. Register, Markus A. Seeliger, Dustin J. Maly
ACS CHEMICAL BIOLOGY
(2020)
Article
Chemistry, Multidisciplinary
Mrinal Shekhar, Zachary Smith, Markus A. Seeliger, Pratyush Tiwary
Summary: Understanding how mutations cause drug resistance is important. In this study, we demonstrate how molecular dynamics simulations can provide a detailed mechanistic explanation for the differences in drug dissociation pathway caused by a mutation. We found that a point mutation in a protein leads to changes in its flexibility, resulting in a faster drug dissociation pathway. We believe that this approach can efficiently explain resistance mutations that are hard to understand from a structural perspective.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Review
Biochemistry & Molecular Biology
Aziz M. Rangwala, Victoria R. Mingione, George Georghiou, Markus A. Seeliger
Summary: Phosphorylation plays a vital role in regulating biological processes, and protein kinases have been extensively studied for their involvement in human health and disease. Some kinases possess additional catalytic functions in addition to phosphotransferase activity, while others have lost their catalytic activity completely. In this study, we analyzed the UniProtKB database for bifunctional protein kinases and focused on those crucial for bacterial and human cellular homeostasis. These kinases have diverse functional roles in environmental sensing, metabolic regulation, immune-host defense, and cell cycle control. This article explores their dual catalytic activities and their contributions to disease pathogenesis.
Article
Biochemistry & Molecular Biology
Alexandra S. Weinheimer, YiTing Paung, Julie Rageul, Arafat Khan, Natalie Lo, Brian Ho, Michael Tong, Sebastien Alphonse, Hyungjin Kim, Markus A. Seeliger
Summary: Elevated DNA replication stress can lead to instability of the DNA replication fork and DNA mutations, which are involved in tumorigenesis. Our study characterizes a new DNA-binding motif in SDE2, called SAP domain, that prefers single-stranded DNA. We also find that SDE2 plays a role in preserving replication fork integrity by regulating the fork protection complex.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Alexander A. Peterson, Aziz M. Rangwala, Manish K. Thakur, Patrick S. Ward, Christie Hung, Ian R. Outhwaite, Alix Chan, Dmitry L. Usanov, Vamsi K. Mootha, Markus A. Seeliger, David R. Liu
Summary: Novel and selective cyclophilin inhibitors have been discovered through in vitro screening, which show high selectivity towards specific subtypes of cyclophilin and can inhibit mitochondrial function. The development of the first inhibitor for a specific cyclophilin subtype further advances the understanding and potential therapeutic applications of these proteins.
NATURE CHEMICAL BIOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Victoria R. Mingione, YiTing Paung, Ian R. Outhwaite, Markus A. Seeliger
Summary: The human genome contains over 500 different protein kinases that have tightly regulated activity as signaling enzymes. The enzymatic activity of the conserved kinase domain is influenced by various regulatory inputs, including the binding of regulatory domains, substrates, and post-translational modifications such as autophosphorylation. This review focuses on the allosteric regulation of protein kinases and highlights recent advances in this field.
BIOCHEMICAL SOCIETY TRANSACTIONS
(2023)
Article
Biochemistry & Molecular Biology
Yagmur Kan, YiTing Paung, Yunyoung Kim, Markus A. Seeliger, W. Todd Miller
Summary: Tyrosine kinases (TKs) are important for regulating cell processes and their dysregulation is linked to various diseases. In this study, novel mutations in the nonreceptor tyrosine kinases Ack1 and Brk were identified in systemic lupus erythematosus (SLE) patients. These mutations resulted in loss of catalytic activity, and their structural impact was further investigated.
Article
Multidisciplinary Sciences
Pelin Ayaz, Agatha Lyczek, YiTing Paung, Victoria R. Mingione, Roxana E. Iacob, Parker W. de Waal, John R. Engen, Markus A. Seeliger, Yibing Shan, David E. Shaw
Summary: The authors used molecular dynamics simulations to study the binding process of Abl kinase with the cancer drug imatinib. The simulations revealed that imatinib induces a large conformational change of the protein and identified a region in Abl kinase that is structurally unstable during binding. Mutations in this region confer imatinib resistance by exacerbating structural instability.
NATURE COMMUNICATIONS
(2023)
Review
Cell Biology
Yagmur Kan, YiTing Paung, Markus A. Seeliger, W. Todd Miller
Summary: The nonreceptor tyrosine kinase Ack1 has a unique arrangement of non-catalytic modules, including an SH3 domain located at the C-terminal of the kinase domain (SH1), which differs from the typical layout in NRTKs. Ack1 shares a region of high homology with the tumor suppressor protein Mig6. It is the only tyrosine kinase family known to carry a UBA domain. The GTPase binding and SAM domains are also uncommon in the NRTKs. Ack1 acts as a downstream effector of receptor tyrosine kinases and integrins, as well as an epigenetic regulator and mediator of drug resistance and hormone-sensitive tumor progression.
Article
Multidisciplinary Sciences
Agatha Lyczek, Benedict-Tilman Berger, Aziz M. Rangwala, YiTing Paung, Jessica Tom, Hannah Philipose, Jiaye Guo, Steven K. Albanese, Matthew B. Robers, Stefan Knapp, John D. Chodera, Markus A. Seeliger
Summary: Protein kinase inhibitors are potent anticancer drugs, but some patients develop resistance to these inhibitors, leading to suboptimal treatment outcomes. Mutations in the Bcr-Abl kinase domain contribute to resistance, with some altering drug-protein interactions and others located far from the drug-binding site still conferring resistance.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biochemistry & Molecular Biology
Sonya M. Hanson, George Georghiou, Manish K. Thakur, W. Todd Miller, Joshua S. Rest, John D. Chodera, Markus A. Seeliger
CELL CHEMICAL BIOLOGY
(2019)