Article
Biochemistry & Molecular Biology
Shadi A. Badiee, Ugochi H. Isu, Ehsaneh Khodadadi, Mahmoud Moradi
Summary: Multidrug resistance (MDR) proteins belonging to the ATP-Binding Cassette (ABC) transporter group play a crucial role in drug resistance and hinder successful treatments. These proteins carry out the transport function through alternating access mechanism involving conformational changes. This review provides an overview of ABC transporters and focuses on well-known mammalian MDR proteins and bacterial counterparts. The review sheds light on the roles of nucleotide-binding domains (NBDs) and transmembrane domains (TMDs), highlights the importance of ATP in the transport process, and discusses recent advancements in the study of MDR proteins and the alternating access mechanism.
Article
Multidisciplinary Sciences
Reza Dastvan, Ali Rasouli, Sepehr Dehghani-Ghahnaviyeh, Samantha Gies, Emad Tajkhorshid
Summary: This study investigates the conformational and proton-dependent dynamics of bacterial Spns protein using lipid membranes. It reveals the critical roles of proton switches and a periplasmic salt bridge in protein activity, and explores the transport mechanism of Spns lipid transporters.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Manuel Wagner, Daniel Blum, Stefanie L. Raschka, Lea-Marie Nentwig, Christoph G. W. Gertzen, Minghao Chen, Christos Gatsogiannis, Andrzej Harris, Sander H. J. Smits, Richard Wagner, Lutz Schmitt
Summary: This study demonstrates that Pdr5, as a multidrug resistance (MDR) efflux pump, not only actively transports substrates across the lipid bilayer, but also generates a proton motif force in the presence of Mg2+-ATP and substrates, thereby increasing its effectiveness.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Narakorn Khunweeraphong, Karl Kuchler
Summary: Multidrug resistance can be a major issue in cancer treatment and microbial infections, with dysregulated overexpression of ATP-binding cassette transporter members being linked to this phenomenon. High-resolution atomic structures from X-ray crystallography or cryo-EM are helping to improve understanding of the mechanisms and dynamics driving these transporters, offering new perspectives for therapeutic interventions.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Multidisciplinary
Michael Rudolph, Robert Tampe, Benesh Joseph
Summary: ATP-binding cassette (ABC) transporters are responsible for transporting various substances across biological membranes. The transition between inward-facing (IF) and outward-facing (OF) conformations of transmembrane domains (TMDs) is crucial for the transport process. This study investigated the functional role of asymmetric nucleotide-binding sites (NBSs) in ABC transporters using pulsed electron-electron double-resonance spectroscopy. The results showed that ATP hydrolysis at the consensus NBS accelerates the reverse transition, and the degenerate NBS may regulate the kinetics of this process.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Pharmacology & Pharmacy
Dingkang Liu, Haibo Rong, Ye Chen, Qun Wang, Sijia Qian, Yue Ji, Wenbing Yao, Jun Yin, Xiangdong Gao
Summary: The engineered therapeutic protein PAK has been found to reverse multidrug resistance in cancer cells, enhancing their sensitivity to chemotherapy. PAK induces mitochondrial injury by selectively inhibiting mitochondrial complex V, leading to redistribution of ABC transporters and reversal of drug resistance.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Yiwen Zhu, Minzheng Gao, Mengrui Su, Yanzhe Shen, Kai Zhang, Bingran Yu, Fu-Jian Xu
Summary: Traditional photodynamic therapy (PDT) is limited in treating deep infections due to insufficient penetration of light and oxygen. A targeting singlet oxygen delivery system, CARG-Py, was designed for irradiation-free and oxygen-free PDT. The system converted to CARG-O-1(2) released singlet oxygen without external irradiation or oxygen and showed potential in efficient treatment of deep infections. This work provides a new strategy to improve traditional PDT for irradiation- and oxygen-free treatment of deep infections while improving convenience.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Review
Medicine, General & Internal
Sanaz Barzegar, Saeed Pirouzpanah
Summary: This review explores how different ZNPs modulate the transcriptional regulation of ABC genes, leading to resistance to cancer therapies. It discusses the potential roles of various ZNPs in promoting MDR through the activation of different signaling pathways.
EUROPEAN JOURNAL OF CLINICAL INVESTIGATION
(2023)
Article
Multidisciplinary Sciences
Elise Kaplan, Nicholas P. Greene, Abigail E. Jepson, Vassilis Koronakis
Summary: In gram-negative bacteria, the Lol system plays a vital role in transporting triacylated lipoproteins from the inner membrane to the outer membrane. LolA, the periplasmic chaperone protein, is crucial for this process. This study presents the crystal structure of liganded LolA, providing molecular details of lipoprotein association and demonstrating how LolA accommodates different lipoproteins by interacting with their acyl chains. Additionally, the comparison of LolA structures reveals that the insertion of lipoprotein acyl chains disrupts the interaction between LolA and LolC. These findings contribute to a better understanding of the trafficking pathway in gram-negative bacteria.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Multidisciplinary Sciences
Tatiana B. Cereija, Joao P. L. Guerra, Joao M. P. Jorge, Joao H. Morais-Cabral
Summary: bis-(3',5')-cyclic diadenosine monophosphate (c-di-AMP) is a second messenger that plays various roles in bacteria, including regulation of virulence, cell wall formation, biofilm formation, and DNA integrity surveillance. It has been shown to have a regulatory effect on the activity of K+ homeostasis machinery, inhibiting K+ import and activating K+ export. Experimental data suggest that c-di-AMP activates KhtTU through a specific mechanism.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Pharmacology & Pharmacy
John Golin, Lutz Schmitt
Summary: Pdr5 is a founding member of a large subfamily of fungal ABC transporters and its remarkable asymmetry is manifested in its ATP-binding sites, drug binding sites, signal transformation interface, and molecular exit gate. The noncanonical ATP site and gating residues in Pdr5 have different essential functions compared to their canonical counterparts.
DRUG RESISTANCE UPDATES
(2023)
Article
Multidisciplinary Sciences
Harlan L. Pietz, Ata Abbas, Zachary Lee Johnson, Michael L. Oldham, Hiroaki Suga, Jue Chen
Summary: This study identifies a macrocyclic peptide CPI1 that inhibits the function of MRP1 and blocks substrate transport. The findings suggest that CPI1 could be a potential therapeutic candidate.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Review
Biochemistry & Molecular Biology
Atsushi Kodan, Ryota Futamata, Yasuhisa Kimura, Noriyuki Kioka, Toru Nakatsu, Hiroaki Kato, Kazumitsu Ueda
Summary: ABCB1, also known as MDR1 or P-glycoprotein, plays a crucial role in exporting various hydrophobic compounds and serving as a protective physiological barrier in several organs. The mechanism involves an aromatic hydrophobic network triggering a conformational change in ABCB1, leading to a twist-and-squeeze motion that exports hydrophobic substrates directly to the extracellular space, distinct from other transporters.
Article
Biochemistry & Molecular Biology
Ingrid Fatima Zattoni, Thales Kronenberger, Diogo Henrique Kita, Lais Danciguer Guanaes, Matheus Murmel Guimaraes, Larissa de Oliveira Prado, Melanie Ziasch, Luis C. Vesga, Fabiane Gomes de Moraes Rego, Geraldo Picheth, Marcos Brown Goncalves, Miguel D. Noseda, Diogo R. B. Ducatti, Antti Poso, Robert W. Robey, Suresh Ambudkar, Vivian Rotuno Moure, Alan Guilherme Goncalves, Glaucio Valdameri
Summary: A newly discovered porphyrin derivative (4B) was identified as an inhibitor of the ABCG2 transporter, capable of overcoming multidrug resistance in vitro and showing selective inhibition towards ABCG2 without being transported by it.
CHEMICO-BIOLOGICAL INTERACTIONS
(2022)
Article
Multidisciplinary Sciences
Tatiana B. Cereija, Joao P. L. Guerra, Joao M. P. Jorge, Joao H. Morais-Cabral
Summary: c-di-AMP is a second messenger that plays important roles in bacterial virulence, cell wall formation, and DNA integrity surveillance. This study provides evidence that c-di-AMP activates the KhtTU component of K+ homeostasis machinery and proposes a mechanism for this activation. Furthermore, the study demonstrates the impact of pH on the sensitivity of KhtTU to c-di-AMP.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Chemistry, Physical
Kalyan Immadisetty, Bin Sun, Peter M. Kekenes-Huskey
Summary: The study compared the binding affinities of different alpha-parvalbumin constructs from the PV family to Ca2+ and Mg2+, revealing that structural features beyond oxygen coordination in the binding loop significantly influence ion binding.
JOURNAL OF PHYSICAL CHEMISTRY B
(2021)
Article
Chemistry, Physical
Kalyan Immadisetty, Mahmoud Moradi
Summary: This study used microsecond-level molecular dynamics simulations to investigate the conformational changes and substrate transport mechanisms in proton-coupled oligopeptide transporters (POTs), shedding light on the structure-function relationship in this important family of transporters.
JOURNAL OF PHYSICAL CHEMISTRY B
(2021)
Article
Chemistry, Physical
Haochuan Chen, Dylan Ogden, Shashank Pant, Wensheng Cai, Emad Tajkhorshid, Mahmoud Moradi, Benoit Roux, Christophe Chipot
Summary: The SMwST algorithm is a method for identifying transition pathways, which is conceptually simple but computationally intensive and requires careful parameter selection. This article presents the theoretical basis, applicability, limitations, and discusses the use of the algorithm in free-energy calculations and kinetics modeling. Through multiple simulations of a prototypical polypeptide, the methodology is examined to optimize computational effort while maintaining accuracy.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2022)
Article
Chemistry, Physical
Vivek Govind Kumar, Shilpi Agrawal, Thallapuranam Krishnaswamy Suresh Kumar, Mahmoud Moradi
Summary: The study reveals that heparin can stabilize hFGF1, with its absence leading to conformational changes and reduced protein stability, providing insights into the mechanistic details of heparin-mediated stabilization. Microsecond-level MD simulations are shown to be effective tools for studying protein structure and dynamics, revealing important biological phenomena that cannot be observed on sub-microsecond time scales.
JOURNAL OF PHYSICAL CHEMISTRY B
(2021)
Article
Biophysics
Kalyan Immadisetty, Josh Alenciks, Peter M. Kekenes-Huskey
Summary: This study investigates how metal-complexed ATP stabilizes the open state of the P2X4 receptor channel and prevents its closing. The presence of Mg2+ and K+ ions at specific binding sites plays a crucial role in maintaining the channel's open conformation. The different capacities of these metal ions to stabilize the channel may govern P2X4 channel gating in physiological systems.
BIOPHYSICAL JOURNAL
(2022)
Article
Biochemistry & Molecular Biology
Vivek Govind Kumar, Dylan S. Ogden, Ugochi H. Isu, Adithya Polasa, James Losey, Mahmoud Moradi
Summary: Within the last 2 decades, two major outbreaks have occurred due to severe acute respiratory syndrome coronaviruses 1 and 2 (SARS-CoV-1 and SARS-CoV-2). However, the 2019 pandemic caused by SARS-CoV-2 has been significantly more widespread than the 2003 SARS epidemic caused by SARS-CoV-1, despite similarities between the two viruses. This study found that the active form of the SARS-CoV-2 spike protein is more stable than that of SARS-CoV-1, and the energy barrier for activation is higher in SARS-CoV-2. These findings suggest that domains other than the receptor-binding domain, such as the N-terminal domain, may play a crucial role in the differential binding behavior of the spike proteins.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Mitchell Benton, Mercede Furr, Vivek Govind Kumar, Adithya Polasa, Feng Gao, Colin David Heyes, Thallapuranam Krishnaswamy Suresh Kumar, Mahmoud Moradi
Summary: The novel protein cpSRP43 plays a unique role in the post-translational chloroplast signal recognition particle (cpSRP) targeting pathway. It acts as a chaperone to LHCPs and can dissolve LHCP aggregates without external energy input. Through computational and experimental techniques, the study reveals that cpSRP43 is simultaneously highly stable and flexible, with different conformations and dynamics when bound to cpSRP54.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Review
Biochemistry & Molecular Biology
Stephanie Sauve, Joseph Williamson, Adithya Polasa, Mahmoud Moradi
Summary: The major facilitator superfamily (MFS) of transporters consists of three classes of membrane transporters: symporters, uniporters, and antiporters. The conformational changes within the distinct transport cycles of MFS transporters are believed to follow the rocker-switch mechanism. This review compares the similarities and differences in conformational dynamics between symporters, uniporters, and antiporters of the MFS family using experimental and computational structural data.
Article
Biochemistry & Molecular Biology
Ugochi H. Isu, Shadi A. Badiee, Ehsaneh Khodadadi, Mahmoud Moradi
Summary: G-protein coupled receptors (GPCRs) play critical roles in various organ systems. Imbalance in cholesterol level affects the structure and function of GPCRs, which is linked to diseases. This review focuses on the interaction, functions, and structural dynamics involved in cholesterol recognition of class C GPCRs.
Article
Biochemistry & Molecular Biology
Shadi A. Badiee, Ugochi H. Isu, Ehsaneh Khodadadi, Mahmoud Moradi
Summary: Multidrug resistance (MDR) proteins belonging to the ATP-Binding Cassette (ABC) transporter group play a crucial role in drug resistance and hinder successful treatments. These proteins carry out the transport function through alternating access mechanism involving conformational changes. This review provides an overview of ABC transporters and focuses on well-known mammalian MDR proteins and bacterial counterparts. The review sheds light on the roles of nucleotide-binding domains (NBDs) and transmembrane domains (TMDs), highlights the importance of ATP in the transport process, and discusses recent advancements in the study of MDR proteins and the alternating access mechanism.
Article
Cardiac & Cardiovascular Systems
Kalyan Immadisetty, Xuan Fang, Geraldine San Ramon, Cassandra M. Hartle, Thomas P. Mccoy, Regeneron Genetics Regeneron Genetics Ctr, Tooraj Mirshahi, Brian P. Delisle, Peter M. Kekenes-Huskey
Summary: This study assessed whether structure-based molecular dynamics simulations and machine learning could improve the identification of missense variants in LQTS-linked genes. By simulating KCNA2 missense variants and studying their impact on Kv11.1 channel protein trafficking, certain molecular features were found to predict trafficking status. Combining bioinformatics data, it was possible to predict with reasonable accuracy which KCNA2 variants do not traffic normally.
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
(2023)
Article
Chemistry, Physical
Curtis Goolsby, James Losey, Ashkan Fakharzadeh, Yuchen Xu, Marie-Christine Duker, Mila Getmansky Sherman, David S. Matteson, Mahmoud Moradi
Summary: Markov State Models (MSM) and related techniques are widely used in molecular dynamics (MD) simulations to extract structural, thermodynamic, and kinetic information on proteins. This work proposes an alternative approach using the rate/generator matrix instead of the transition matrix for estimating thermodynamic and kinetic quantities, particularly in diffusive processes. The key contribution of this work is the introduction of a novel method to address the embeddability problem and the utilization of existing algorithms. The algorithms are tested on a one-dimensional toy model to demonstrate their effectiveness and robustness.
JOURNAL OF PHYSICAL CHEMISTRY A
(2023)
Article
Computer Science, Interdisciplinary Applications
Vivek Govind Kumar, Adithya Polasa, Shilpi Agrawal, Thallapuranam Krishnaswamy Suresh Kumar, Mahmoud Moradi
Summary: The protein-ligand binding affinity can be quantified to measure the strength of binding between a protein and its ligand. In this paper, a purely physics-based sampling approach using biased molecular dynamics simulations is presented. The approach simplifies previously suggested strategies and can be tailored for any system of interest. The binding affinity of human fibroblast growth factor 1 to heparin hexasaccharide is estimated using four variations of the proposed method and compared against experimentally determined binding affinity.
NATURE COMPUTATIONAL SCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Kalyan Immadisetty, Adithya Polasa, Reid Shelton, Mahmoud Moradi
Summary: This study elucidates the activation mechanism of an engineered MscL at an atomic level and reveals the key roles of periplasmic loops and the loss of various peptide interactions in the activation process. The findings provide insights for engineering more efficient pH-sensing mechanosensitive channels.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2022)
Article
Chemistry, Multidisciplinary
Adithya Polasa, Imann Mosleh, James Losey, Alireza Abbaspourrad, Robert Beitle, Mahmoud Moradi
Summary: This study investigates the formation of nanoparticles using a specific peptide and its variants in both isolated and fused states. The results show that the presence of a protein reduces the sensitivity of nanoparticles to the peptide sequence, allowing for the synthesis of nanoparticles with well-regulated properties.
NANOSCALE ADVANCES
(2022)