Article
Multidisciplinary Sciences
Rajkama, Nisal, P. Jitendra, Agata, Susan, Geoff, W. Aaron, J. Anita, Namita Roy, K. Naba
Summary: This study reveals the impact of crowding on the dynamic conformation of intrinsically disordered proteins (IDPs). Through experimental methods and model construction, researchers found that crowding can induce specific conformational changes in IDPs. This study is of great importance for a better understanding of the interactions and structural dynamics of IDPs in crowded environments.
Article
Biochemistry & Molecular Biology
Xi Wang, Harry M. Greenblatt, Lavi S. Bigman, Binhan Yu, Channing C. Pletka, Yaakov Levy, Junji Iwahara
Summary: This study investigates how D/E repeats cause autoinhibition of HMGB1 and its specific binding to cisplatin-modified DNA. By varying ionic strength, the conformational equilibrium between autoinhibited and uninhibited states can be shifted, revealing fuzzy interactions of D/E repeats with other intrinsically disordered regions. Mutations mimicking post-translational modifications relevant to nuclear export of HMGB1 can moderately modulate DNA-binding affinity, possibly by impacting the autoinhibition.
JOURNAL OF MOLECULAR BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Ilinka Clerc, Amin Sagar, Alessandro Barducci, Nathalie Sibille, Pau Bernado, Juan Cortes
Summary: Intrinsically disordered proteins and regions play crucial roles in biological processes by performing specialized functions related to the recognition of other biomolecules. Computational approaches have become essential tools for understanding the functional mechanisms of these proteins due to their conformational heterogeneity.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2021)
Article
Biochemistry & Molecular Biology
Lynn G. Schrag, Xiaorong Liu, Indhujah Thevarajan, Om Prakash, Michal Zolkiewski, Jianhan Chen
Summary: Intrinsically disordered proteins play crucial roles in cell decision making and regulatory networks; cancer-associated mutations in p53-TAD can significantly disrupt the balance of interactions with regulatory proteins; these mutations may modulate the disordered state of p53-TAD to perturb interactions with regulators.
JOURNAL OF MOLECULAR BIOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Rakesh Trivedi, Hampapathalu Adimurthy Nagarajaram
Summary: This review discusses different aspects of disordered proteins and protein regions, as well as the experimental and computational methods used to characterize them. Additionally, the role of disordered proteins in diseases and their potential as drug targets are explored.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Multidisciplinary
Valentin Bauer, Boris Schmidtgall, Gergo Gogl, Jozica Dolenc, Judit Osz, Yves Nomine, Camille Kostmann, Alexandra Cousido-Siah, Andre Mitschler, Natacha Rochel, Gilles Trave, Bruno Kieffer, Vladimir Torbeev
Summary: This study utilized a specific amino acid substitution pattern to modify the free activation domain of transcriptional coactivator ACTR, resulting in increased binding affinity to CREB-binding protein. The X-ray structure of the modified ACTR domain - NCBD complex revealed a unique conformation of ACTR, demonstrating a strategy for characterizing individual conformational states of IDPs.
Review
Chemistry, Multidisciplinary
Aldo R. Camacho-Zarco, Vincent Schnapka, Serafima Guseva, Anton Abyzov, Wiktor Adamski, Sigrid Milles, Malene Ringkjobing Jensen, Lukas Zidek, Nicola Salvi, Martin Blackledge
Summary: This review introduces the applications of nuclear magnetic resonance (NMR) in understanding the structure, dynamic behavior, and interaction trajectories of intrinsically disordered proteins. NMR provides ensemble averaged structural and dynamic parameters for each assigned resonance, revealing the importance of these parameters in the kinetics and thermodynamics of cellular and extracellular reactions. Furthermore, NMR can uncover the mechanistic basis of functional disordered molecular assemblies that are crucial for human health.
Review
Chemistry, Multidisciplinary
Aldo R. Camacho-Zarco, Vincent Schnapka, Serafima Guseva, Anton Abyzov, Wiktor Adamski, Sigrid Milles, Malene Ringkjobing Jensen, Lukas Zidek, Nicola Salvi, Martin Blackledge
Summary: Intrinsically disordered proteins play essential roles in cellular and extracellular biochemistry. Nuclear magnetic resonance is a powerful tool for studying their structural and dynamic behavior, providing insights into reaction kinetics and thermodynamics essential for function. Recent applications of NMR have helped uncover the mechanistic basis of functional disordered molecular assemblies important for human health.
Review
Biochemistry & Molecular Biology
H. Jane Dyson
Summary: Viruses infect all kingdoms of life and employ disordered proteins to accomplish various functions. Disordered proteins have been discovered in almost all viruses studied, regardless of the viral genome composition or the viral capsid configuration. This review presents a collection of stories illustrating the diverse functions of disordered proteins in viruses, providing a survey of the field's expansion.
JOURNAL OF MOLECULAR BIOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Samuel Naudi-Fabra, Maud Tengo, Malene Ringkjobing Jensen, Martin Blackledge, Sigrid Milles
Summary: Studying the conformational landscape of intrinsically disordered and partially folded proteins is challenging and requires an integrated approach using multiple techniques to accurately describe the conformational ensembles of these proteins. This integrated approach has been successfully tested and validated, providing new insights into the conformational landscape of viral proteins and demonstrating its potential for integrative dynamic structural biology.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Biochemistry & Molecular Biology
Nicolas Palopoli, Julia Marchetti, Alexander M. Monzon, Diego J. Zea, Silvio C. E. Tosatto, Maria S. Fornasari, Gustavo Parisi
Summary: This study reveals that intrinsically disordered proteins (IDPs) evolve under strong site-specific evolutionary rate heterogeneity, mainly due to different constraints from their inter-residue contacts. Evolutionary rate profiles correlate with the experimentally observed conformational diversity, allowing the description of different conformational patterns possibly related to their structure-function relationships.
JOURNAL OF MOLECULAR BIOLOGY
(2021)
Article
Multidisciplinary Sciences
Thinh D. N. Luong, Suhani Nagpal, Mourad Sadqi, Victor Munoz
Summary: This article introduces a method called "Molecular LEGO" that allows for the dissection of conformational landscapes of unbound intrinsically disordered proteins (IDPs) and provides insights into the functional mechanisms of these proteins. The method was applied to the protein NCBD and revealed specific energetic biases and conformational rheostatic behavior in NCBD's folding landscape, which are likely crucial for its function as a transcriptional coactivator.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Review
Biochemistry & Molecular Biology
David Moses, Garrett M. Ginell, Alex S. Holehouse, Shahar Sukenik
Summary: Intrinsically disordered proteins and protein regions (IDRs) play essential roles in eukaryotic organisms. Unlike folded proteins, IDRs exist in a conformational ensemble influenced by sequence-dependent interactions. The absence of a stable 3D structure and high solvent accessibility make IDRs inherently sensitive to environmental changes, allowing them to act as sensors and actuators of cellular physicochemistry.
TRENDS IN BIOCHEMICAL SCIENCES
(2023)
Article
Chemistry, Multidisciplinary
Dan Wang, Shaowen Wu, Dongdong Wang, Xingyu Song, Maohua Yang, Wolun Zhang, Shaohui Huang, Jingwei Weng, Zhijun Liu, Wenning Wang
Summary: This study investigates the interaction mechanism between protein 4.1G-CTD and NuMA using experimental and computational methods. The results demonstrate the importance of the compact disordered state of 4.1G-CTD for its binding to NuMA. This work sheds light on the molecular recognition mechanism of intrinsically disordered proteins/regions (IDPs/IDRs) and expands the conventional structure-function paradigm in protein biochemistry.
Review
Biochemistry & Molecular Biology
Rachel Evans, Sravani Ramisetty, Prakash Kulkarni, Keith Weninger
Summary: Intense study of intrinsically disordered proteins (IDPs) began in the late 1990s and revealed their important functions. Over the past two decades, it has become clear that IDPs play critical roles in various biological phenomena. The application of integrative structural biology has emerged as an essential approach to understanding IDP phenomena.
Article
Chemistry, Physical
Adam R. Offenbacher, Bridgette A. Barry
JOURNAL OF PHYSICAL CHEMISTRY B
(2020)
Article
Chemistry, Physical
Kristin J. Tyson, Amanda N. Davis, Jessica L. Norris, Libero J. Bartolotti, Eli G. Hvastkovs, Adam R. Offenbacher
JOURNAL OF PHYSICAL CHEMISTRY LETTERS
(2020)
Review
Biochemistry & Molecular Biology
Adam R. Offenbacher, Theodore R. Holman
Article
Biochemistry & Molecular Biology
Wan-Chen Tsai, Ansari Mukhtar Aleem, Chris Whittington, Wilian A. Cortopassi, Chakrapani Kalyanaraman, Angel Baroz, Anthony T. Iavarone, Ewa Skrzypczak-Jankun, Matthew P. Jacobson, Adam R. Offenbacher, Theodore Holman
Summary: Through computational modeling, experimental mutagenesis, and hydrogen-deuterium exchange (HDX) investigations, this study reveals the dimeric structure of human platelet 12S-lipoxygenase (h12-LOX). Experimental results demonstrate that mutations in specific amino acid residues affect dimer formation of h12-LOX, further validating the accuracy of the computational model.
Article
Chemistry, Physical
Ryan Atlee Watson, Adam R. Offenbacher, Bridgette A. Barry
Summary: Ribonucleotide reductase (RNR) is essential for DNA synthesis and consists of two subunits, alpha(2) and beta(2), which form an active complex alpha(2)beta(2) through a PCET pathway. The RIFTIR spectroscopic method provides new insights into the mechanism of active RNR complex, revealing conformational changes and the role of inhibitors in enzyme activity. This method helps detect subtle conformational motions and reveal the complex dynamics involved in RNR catalysis.
JOURNAL OF PHYSICAL CHEMISTRY B
(2021)
Article
Chemistry, Physical
Mohammad S. Safiarian, R. Atlee Watson, Raquel L. Lieberman, Bridgette A. Barry, Adam R. Offenbacher
Summary: Ribonucleotide reductase (RNR) plays a crucial role in DNA biosynthesis and repair, and has been associated with human diseases, making it a potential therapeutic target. Triapine, a small molecule inhibitor, has been shown to effectively inhibit the tyrosyl radical within the RNR beta(2) subunit, providing insight into its mechanism of action. These findings suggest the potential for further development of RNR inactivators based on the triapine scaffold for therapeutic applications.
JOURNAL OF PHYSICAL CHEMISTRY LETTERS
(2021)
Article
Biochemistry & Molecular Biology
Daniella E. Roberts, Amy M. Benton, Claire Fabian-Bayola, Anne M. Spuches, Adam R. Offenbacher
Summary: This study reveals that the allosteric regulation of soybean lipoxygenase (SLO) by fatty acids is controlled by the dynamics of helix alpha 2, using isothermal titration calorimetry.
Article
Biochemistry & Molecular Biology
Grega Popovic, Nicholas C. Kirby, Taylor C. Dement, Kristine M. Peterson, Caroline E. Daub, Heather A. Belcher, Martin Guthold, Adam R. Offenbacher, Nathan E. Hudson
Summary: This study tests a transient expression system for high-yield production of fibrinogen and proposes an affinity-based purification method. The establishment of these methods contributes to future studies on fibrinogen and the utilization of fibrin as a biomaterial.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Multidisciplinary
Courtney L. Labrecque, Aubree L. Nolan, Angela M. Develin, Abdul J. Castillo, Adam R. Offenbacher, Brian Fuglestad
Summary: Despite advances in the study of membrane proteins, there is still limited high-resolution information about peripheral membrane proteins and their interactions with membranes and lipids. This study presents the development of phosphocholine-based systems that mimic biological membranes and are compatible with high-resolution protein NMR, providing a new tool for the study of elusive PMP interactions and other membrane interfacial investigations.
Article
Biochemistry & Molecular Biology
Michelle Tran, Rachel L. Signorelli, Adriana Yamaguchi, Eefie Chen, Michael Holinstat, Anthony T. Iavarone, Adam R. Offenbacher, Theodore Holman
Summary: This study investigates the impact of a single nucleotide polymorphism (SNP) in the h12-LOX gene on the structure, dynamics, and function of the protein. The findings reveal subtle changes in activity, membrane affinity, and protein stability caused by the SNP, which play significant physiological roles in platelet biology.
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
(2023)
Article
Chemistry, Physical
Kristin Tyson, Chanin B. Tangtartharakul, Matthias Zeug, Nathan Findling, Alice Haddy, Eli Hvastkovs, Jun-yong Choe, Judy E. Kim, Adam R. Offenbacher
Summary: This study investigates the electrochemical properties of tryptophan in proteins and finds that the presence of water molecules increases its electrochemical potential. Additionally, UV resonance Raman spectroscopy data reveal the characteristics of the local hydrogen bonding environment of tryptophan.
JOURNAL OF PHYSICAL CHEMISTRY B
(2022)
Article
Biochemistry & Molecular Biology
Ajay Sharma, Chris Whittington, Mohammed Jabed, S. Gage Hill, Anastasiia Kostenko, Tao Yu, Pengfei Li, Peter E. Doan, Brian M. Hoffman, Adam R. Offenbacher
Summary: We report the active-site structure of the MoLOX substrate complex, which provides insight into reactivity differences across the LOX family and can guide the development of MoLOX inhibitors. The ENDOR-guided MD approach used in this study demonstrates its robustness in describing LOX-substrate structures.
Article
Biochemistry & Molecular Biology
Luis Guevara, Melissa Gouge, Amanda Ohler, S. Gage Hill, Soham Patel, Adam R. Offenbacher
Summary: Hydrogen tunneling in enzyme reactions plays an important role in connecting protein thermal motions to catalysis. This study investigated the effect of solvent viscosity on protein thermal motions in lipoxygenases (LOXs) and found that viscosity does not affect the catalytic reaction of soybean lipoxygenase (SLO), but inhibits the activity of 15LOX-2. These findings provide insights into the role of water hydration layers in hydrogen tunneling in LOX.
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
(2023)
Article
Hematology
Jose E. E. Pinelo, Pragya Manandhar, Grega Popovic, Katherine Ray, Mehmet F. Tasdelen, Quoc Nguyen, Anthony T. Iavarone, Adam R. Offenbacher, Nathan E. Hudson, Mehmet Sen
Summary: Using multiple biophysical methods, we obtained a conformational dynamic model of human fibrinogen in solution, revealing four distinct conformations and a high degree of internal protein flexibility. This provides a molecular basis for the functional diverse macromolecular interactions and mechanical properties of blood clots.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2023)
Article
Chemistry, Multidisciplinary
Amanda Ohler, Hanna Long, Kei Ohgo, Kristin Tyson, David Murray, Amanda Davis, Chris Whittington, Eli G. Hvastkovs, Liam Duffy, Alice Haddy, Andrew L. Sargent, William E. Allen, Adam R. Offenbacher
Summary: Fluorinated 5-hydroxytryptophans were synthesized and incorporated into a beta-hairpin peptide and the protein azurin, demonstrating unique radical spectroscopic signatures and expanding their function as probes for biological electron transfer.
CHEMICAL COMMUNICATIONS
(2021)