The AAA+ ATPase p97 as a novel parasite and tuberculosis drug target

Kobakhidze, George; Sethi, Ashish; Valimehr, Sepideh; Ralph, Stuart A.; Rouiller, Isabelle

doi:10.1016/j.pt.2022.03.004

Cited by 4 publications

(5 citation statements)

References 104 publications

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“…In another study, Kobakhidze et al. used models from the AlphaFold database or directly generated predictions using the Google Colab to investigate whether AAA+ ATPase p97 would be a potential, novel target implicated both in tuberculosis and parasitology [53].…”

Section: Resultsmentioning

confidence: 99%

The impact of AlphaFold Protein Structure Database on the fields of life sciences

Váradi

Velankar

2022

Proteomics

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Arguably, 2020 was the year of high‐accuracy protein structure predictions, with AlphaFold 2.0 achieving previously unseen accuracy in the Critical Assessment of Protein Structure Prediction (CASP). In 2021, DeepMind and EMBL‐EBI developed the AlphaFold Protein Structure Database to make an unprecedented number of reliable protein structure predictions easily accessible to the broad scientific community.We provide a brief overview and describe the latest developments in the AlphaFold database. We highlight how the fields of data services, bioinformatics, structural biology, and drug discovery are directly affected by the influx of protein structure data. We also show examples of cutting‐edge research that took advantage of the AlphaFold database. It is apparent that connections between various fields through protein structures are now possible, but the amount of data poses new challenges.Finally, we give an outlook regarding the future direction of the database, both in terms of data sets and new functionalities.

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Section: Resultsmentioning

confidence: 99%

The impact of AlphaFold Protein Structure Database on the fields of life sciences

Váradi

Velankar

2022

Proteomics

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“…We have also described some mechanisms known to regulate its activity. A better understanding of these regulatory mechanisms is essential for designing more specific therapeutic drugs targeting p97 for the treatment of cancer, neurological diseases and potentially infectious diseases, including parasitic diseases [9]. It is worth noting that our current understanding of the functions of p97 is based on bulk studies and average structures.…”

Section: Discussion and Future Perspectivesmentioning

confidence: 99%

“…Present in all organisms, AAA+ ATPases function by converting the chemical energy released from ATP hydrolysis into mechanical force, enabling these enzymes to perform a variety of cellular functions [2]. A prominent member of this family is the protein named p97 or VCP in mammalian and plant cells, with orthologs in all kingdoms of life, including Mycobacterium smegmatis (Msm0858, also known as MsmCpa), Leishmania infantium (LiVCP), Trypanosoma brucei (tbVCP), Thermoplasma acidophilum (VAT), Saccharomyces cerevisiae (Cdc48) and Drosophila melanogaster (TER94) [3][4][5][6][7][8][9]. p97 is one of the most abundant cytosolic proteins in all eukaryotic cells and has been shown to play a central role in gene expression regulation, organelle and protein biogenesis, and homeostasis.…”

Section: Introduction 1general Introductionmentioning

confidence: 99%

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Molecular Mechanisms Driving and Regulating the AAA+ ATPase VCP/p97, an Important Therapeutic Target for Treating Cancer, Neurological and Infectious Diseases

et al. 2023

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p97/VCP, a highly conserved type II ATPase associated with diverse cellular activities (AAA+ ATPase), is an important therapeutic target in the treatment of neurodegenerative diseases and cancer. p97 performs a variety of functions in the cell and facilitates virus replication. It is a mechanochemical enzyme that generates mechanical force from ATP-binding and hydrolysis to perform several functions, including unfolding of protein substrates. Several dozens of cofactors/adaptors interact with p97 and define the multifunctionality of p97. This review presents the current understanding of the molecular mechanism of p97 during the ATPase cycle and its regulation by cofactors and small-molecule inhibitors. We compare detailed structural information obtained in different nucleotide states in the presence and absence of substrates and inhibitors. We also review how pathogenic gain-of-function mutations modify the conformational changes of p97 during the ATPase cycle. Overall, the review highlights how the mechanistic knowledge of p97 helps in designing pathway-specific modulators and inhibitors.

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“…Mutations in the p97 gene have been associated with the development of multisystem proteinopathy (MSP) in humans, with the pathological accumulation of protein aggregates in the brain, muscle, and bone [ 25 , 26 , 27 , 28 ]. p97 has also been identified as a target for the treatment of cancer and neurological, viral, and parasitic diseases [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. p97 assembles as a homohexamer with a quaternary structure in the shape of a double-stacked ring in the absence of a substrate [ 14 , 37 ].…”

Section: Introductionmentioning

confidence: 99%

Analysis of the Conformational Landscape of the N-Domains of the AAA ATPase p97: Disentangling the Continuous Conformational Variability in Partially Symmetrical Complexes

Valimehr,

Vuillemot,

Kazemi

et al. 2024

IJMS

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Single-particle cryo-electron microscopy (cryo-EM) has been shown to be effective in defining the structure of macromolecules, including protein complexes. Complexes adopt different conformations and compositions to perform their biological functions. In cryo-EM, the protein complexes are observed in solution, enabling the recording of images of the protein in multiple conformations. Various methods exist for capturing the conformational variability through analysis of cryo-EM data. Here, we analyzed the conformational variability in the hexameric AAA + ATPase p97, a complex with a six-fold rotational symmetric core surrounded by six flexible N-domains. We compared the performance of discrete classification methods with our recently developed method, MDSPACE, which uses 3D-to-2D flexible fitting of an atomic structure to images based on molecular dynamics (MD) simulations. Our analysis detected a novel conformation adopted by approximately 2% of the particles in the dataset and determined that the N-domains of p97 sway by up to 60° around a central position. This study demonstrates the application of MDSPACE in analyzing the continuous conformational changes in partially symmetrical protein complexes, systems notoriously difficult to analyze due to the alignment errors caused by their partial symmetry.

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The AAA+ ATPase p97 as a novel parasite and tuberculosis drug target

Cited by 4 publications

References 104 publications

The impact of AlphaFold Protein Structure Database on the fields of life sciences

The impact of AlphaFold Protein Structure Database on the fields of life sciences

Molecular Mechanisms Driving and Regulating the AAA+ ATPase VCP/p97, an Important Therapeutic Target for Treating Cancer, Neurological and Infectious Diseases

Analysis of the Conformational Landscape of the N-Domains of the AAA ATPase p97: Disentangling the Continuous Conformational Variability in Partially Symmetrical Complexes

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