Exploring Purine Analogues as Inhibitors against Katanin, a Microtubule Severing Enzyme using Molecular Modeling Approach DOI Creative Commons
Bajarang Vasant Kumbhar,

V. S. Saxena,

Pruthanka Patil

и другие.

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Авг. 9, 2024

Abstract Katanin, a pioneering microtubule-severing enzyme, is novel AAA-ATPase protein. It severs microtubules by forming hexamers that binds to the C-terminal tails of tubulin, using ATP hydrolysis generate force necessary break microtubule lattice. Katanin contributes amplification and impact growth carcinomas. Hence, katanin highly promising target for anti-cancer drug development. This study aims identify potential purine-based inhibitors against structure-based virtual screening, PASS ADME-T prediction, docking, molecular dynamics simulations. Here, library 2,76,280 compounds from PubChem Database were utilized, top two purine type (PubChem ID: 122589735, 123629569) selected based on superior binding energy, ADME-T, biological activity. Furthermore, docking simulations revealed 122589735 123629569 effectively alter katanin's structure as compared ATP. Besides, energy calculations indicate exhibits higher affinity with Thus, our computational identifies exhibit than may have implications various research paves way developing novel, therapies targeting range carcinoma types.

Язык: Английский

Combinatorial and antagonistic effects of tubulin glutamylation and glycylation on katanin microtubule severing DOI Creative Commons
Ewa Szczęsna, Elena A. Zehr,

Steven W. Cummings

и другие.

Developmental Cell, Год журнала: 2022, Номер 57(21), С. 2497 - 2513.e6

Опубликована: Ноя. 1, 2022

Язык: Английский

Процитировано

33
CAMSAP1 role in orchestrating structure and dynamics of manchette microtubule minus-ends impacts male fertility during spermiogenesis DOI Creative Commons

Weichang Hu,

Rui Zhang, Honglin Xu

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2023, Номер 120(45)

Опубликована: Окт. 30, 2023

The manchette is a crucial transient structure involved in sperm development, with its composition and regulation still not fully understood. This study focused on investigating the roles of CAMSAP1 CAMSAP2, microtubule (MT) minus-end binding proteins, regulating MTs, spermiogenesis, male fertility. loss CAMSAP1, but disrupts well-orchestrated process leading to abnormal elongation delayed removal, resulting deformed nuclei tails resembling oligoasthenozoospermia symptoms. We investigated underlying molecular mechanisms by purifying assemblies comparing them through proteomic analysis, results showed that absence disrupted proper localization key proteins (CEP170 KIF2A) at minus end, compromising structural integrity hindering MT depolymerization. These findings highlight significance maintaining homeostasis minus-ends for shaping morphology during late offering insights into infertility abnormalities.

Язык: Английский

Процитировано

15
Dual-target inhibitors of colchicine binding site for cancer treatment DOI
Lu Lu, Keke Li,

Jiaxin Pu

и другие.

European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 274, С. 116543 - 116543

Опубликована: Май 31, 2024

Язык: Английский

Процитировано

6
Microtubule-severing enzymes DOI Creative Commons
Stephanie L. Sarbanes, Elena A. Zehr, Antonina Roll‐Mecak

и другие.

Current Biology, Год журнала: 2022, Номер 32(19), С. R992 - R997

Опубликована: Окт. 1, 2022

Язык: Английский

Процитировано

22
Manipulation of Host Microtubule Networks by Viral Microtubule-Associated Proteins DOI Creative Commons
Dahee Seo, Don B. Gammon

Viruses, Год журнала: 2022, Номер 14(5), С. 979 - 979

Опубликована: Май 6, 2022

Diverse DNA and RNA viruses utilize cytoskeletal networks to efficiently enter, replicate, exit the host cell, while evading immune responses. It is well established that microtubule (MT) network commonly hijacked by traffic sites of replication after entry promote egress from cell. However, mounting evidence suggests MT also a key regulator responses infection. At same time, have acquired mechanisms manipulate and/or usurp evade these Central most interactions with are virally encoded microtubule-associated proteins (MAPs) bind MTs directly or indirectly. These MAPs associate other viral cellular regulate various aspects network, including dynamics, MT-dependent transport via motor such as kinesins dyneins, regulation innate In this review, we examine how MAP facilitate evasion.

Язык: Английский

Процитировано

18
The multifaceted roles of microtubule-associated proteins in the primary cilium and ciliopathies DOI Creative Commons
Jovana Deretic, Ezgi Odabasi, Elif Nur Firat‐Karalar

и другие.

Journal of Cell Science, Год журнала: 2023, Номер 136(23)

Опубликована: Дек. 1, 2023

ABSTRACT The primary cilium is a conserved microtubule-based organelle that critical for transducing developmental, sensory and homeostatic signaling pathways. It comprises an axoneme with nine parallel doublet microtubules extending from the basal body, surrounded by ciliary membrane. exhibits remarkable stability, serving as skeleton of in order to maintain its shape provide tracks trafficking complexes. Although have been exhaustively characterized over years, less known about unique structural functional complexities axoneme. Recent work has yielded new insights into mechanisms which built proper length architecture, particularly regarding activity microtubule-associated proteins (MAPs). In this Review, we first summarize current knowledge composition specialized compartments cilium. Next, discuss mechanistic underpinnings how assembled, maintained disassembled through regulation axonemal microtubules. We conclude examining diverse localizations functions MAPs pathobiology diseases.

Язык: Английский

Процитировано

10
Discovery of Novel Diaryl-Substituted Fused Heterocycles Targeting Katanin and Tubulin with Potent Antitumor and Antimultidrug Resistance Efficacy DOI

Fuhao Jiang,

Min Yu, Yuru Liang

и другие.

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(14), С. 12118 - 12142

Опубликована: Июль 12, 2024

Disrupting microtubule dynamics has emerged as a promising strategy for cancer treatment. However, drug resistance remains challenge hindering the development of microtubule-targeting agents. In this work, novel class diaryl substituted fused heterocycles were designed, synthesized, and evaluated, which demonstrated effective dual katanin tubulin regulators with antitumor activity. Following three rounds stepwise optimization, compound 21b, featuring 3H-imidazo[4,5-b]pyridine core, displayed excellent targeting capabilities on tubulin, along notable antiproliferative antimetastatic effects. Mechanistic studies revealed that 21b disrupts network in tumor cells, leading to G2/M cell cycle arrest apoptosis induction. Importantly, exhibited significant inhibition growth MDA-MB-231 A549/T xenograft models without evident toxicity side conclusion, presents mechanism disrupting dynamics, warranting further investigation dual-targeted agent potential antimultidrug properties.

Язык: Английский

Процитировано

4
Microtubule-binding domains in Katanin p80 subunit are essential for severing activity in C. elegans DOI Creative Commons
Eva Beaumale, Lucie Van Hove, Lionel Pintard

и другие.

The Journal of Cell Biology, Год журнала: 2024, Номер 223(4)

Опубликована: Фев. 8, 2024

Microtubule-severing enzymes (MSEs), such as Katanin, Spastin, and Fidgetin play essential roles in cell division neurogenesis. They damage the microtubule (MT) lattice, which can either destroy or amplify MT cytoskeleton, depending on cellular context. However, little is known about how they interact with their substrates. We have identified microtubule-binding domains (MTBD) required for Katanin function C. elegans. a heterohexamer of dimers containing catalytic subunit p60 regulatory p80, both are female meiotic spindle assembly. Here, we report that p80-like(MEI-2) dictates binding to MTs via two MTBDs composed basic patches. Substituting these patches reduces MTs, compromising its meiotic-spindle Structural alignments p80s from different species revealed evolutionarily conserved, even if specific amino acids involved vary. Our findings highlight critical importance (p80) providing complex.

Язык: Английский

Процитировано

3
GPI transamidase complex is required for primordial germ cell migration and development in zebrafish DOI Creative Commons
Weiying Zhang,

Yaqi Li,

Jing Chen

и другие.

Journal of Molecular Cell Biology, Год журнала: 2024, Номер unknown

Опубликована: Дек. 31, 2024

Abstract Proteins without transmembrane domains could be anchored to the cell surface for regulating various biological processes when covalently linked glycosylphosphatidylinositol (GPI) molecules by GPI transamidase (GPIT) complex. However, it remains poorly understood whether and how GPIT complex affects primordial germ (PGC) development. In this study, we report important roles of in PGC migration development zebrafish embryos. Mutation pigu or pigk, both encoding essential subunits, resulted defective with ectopically located PGCs reduction counts. Notably, a detailed analysis filopodia revealed attenuated polarity distribution along direction mutant transplantation PGC-specific rescue experiments demonstrated that somatic cell-expressed Pigu are required migration. Furthermore, expression levels genes decreased derepression genes. Hence, propose plays critical role during

Язык: Английский

Процитировано

3
The quaternary question: Determining allostery in spastin through dynamics classification learning and bioinformatics DOI Open Access
Maria S. Kelly, Amanda C. Macke, Shehani Kahawatte

и другие.

The Journal of Chemical Physics, Год журнала: 2023, Номер 158(12)

Опубликована: Март 7, 2023

The nanomachine from the ATPases associated with various cellular activities superfamily, called spastin, severs microtubules during processes. To characterize functionally important allostery in we employed methods evolutionary information, to graph-based networks, machine learning applied atomistic molecular dynamics simulations of spastin its monomeric and functional hexameric forms, presence or absence ligands. Feature selection, using approaches, for transitions between states recognizes all regions that have been proposed as allosteric literature. analysis composition Markov State Model macrostates monomer, direction change top features transitions, indicate monomer favors binding ATP, which primes involved formation inter-protomer interfaces other protomer(s). Allosteric path graph built based on cross-correlations residues simulations, shows perturbations a hub specific pre-hydrolysis hexamer propagate throughout structure by passing through two obligatory regions: ATP pocket, pore loop 3, connects substrate site site. Our findings support model where changes terminal protomers due ligands play an active role force generation spastin. secondary structures are found be highly degenerative within network paths, also critical feature classification models, can guide design effectors enhance block signaling.

Язык: Английский

Процитировано

7