Pioneer in Molecular Biology: Conformational Ensembles in Molecular Recognition, Allostery, and Cell Function DOI
Ruth Nussinov

Published: Jan. 1, 2024

Language: Английский

Allostery in Disease: Anticancer Drugs, Pockets, and the Tumor Heterogeneity Challenge DOI Creative Commons
Ruth Nussinov, Bengi Ruken Yavuz, Hyunbum Jang

et al.

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 169050 - 169050

Published: Feb. 1, 2025

Language: Английский

Citations

2
mTOR Variants Activation Discovers PI3K-like Cryptic Pocket, Expanding Allosteric, Mutant-Selective Inhibitor Designs DOI
Yonglan Liu, Wengang Zhang, Hyunbum Jang

et al.

Journal of Chemical Information and Modeling, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 10, 2025

mTOR plays a crucial role in PI3K/AKT/mTOR signaling. We hypothesized that activation mechanisms driving oncogenesis can advise effective therapeutic designs. To test this, we combined cancer genomic analysis with extensive molecular dynamics simulations of oncogenic variants. observed conformational changes within kinase domain are associated multiple mutational events. The mutations disturb the α-packing formed by kαAL, kα3, kα9, kα9b, and kα10 helices domain, creating cryptic pocket. Its opening correlates catalytic cleft, including active site residues realignment, favoring catalysis. pocket created disrupted coincides allosteric PI3Kα be harmoniously fitted inhibitor RLY-2608, suggesting analogous drugs designed based on RLY-2608 restore packed α-structure, resulting inactive conformation. Our results exemplify knowledge detailed inform innovative development.

Language: Английский

Citations

1
Identification and Understanding of Allostery Hotspots in Proteins: Integration of Deep Mutational Scanning and Multi-faceted Computational Analyses DOI
Qiang Cui

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 168998 - 168998

Published: Feb. 1, 2025

Language: Английский

Citations

0
Resistance to Allosteric Inhibitors DOI
Ian R Outhwaite,

Isabelle Kwan,

Neil P. Shah

et al.

Published: Jan. 1, 2025

Citations

0
Pioneer in Molecular Biology: Conformational Ensembles in Molecular Recognition, Allostery, and Cell Function DOI Creative Commons
Ruth Nussinov

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 169044 - 169044

Published: Feb. 1, 2025

Language: Английский

Citations

0
Integrative Computational Analysis of Common EXO5 Haplotypes: Impact on Protein Dynamics, Genome Stability, and Cancer Progression DOI Creative Commons

F. Mazza,

Davide Dalfovo, Alessio Bartocci

et al.

Journal of Chemical Information and Modeling, Journal Year: 2025, Volume and Issue: unknown

Published: March 21, 2025

Understanding the impact of common germline variants on protein structure, function, and disease progression is crucial in cancer research. This study presents a comprehensive analysis EXO5 gene, which encodes DNA exonuclease involved repair that was previously associated with susceptibility. We employed an integrated approach combining genomic clinical data analysis, deep learning variant effect prediction, molecular dynamics (MD) simulations to investigate effects haplotypes dynamics, outcomes. characterized haplotype structure across diverse human populations, identifying five haplotypes, studied their protein. Extensive, all-atom MD revealed significant structural dynamic differences among variants, particularly catalytic region. The L151P exhibited most substantial conformational changes, potentially disruptive for EXO5′s function nuclear localization. Analysis Cancer Genome Atlas showed patients carrying had significantly shorter progression-free survival prostate pancreatic cancers increased instability. highlights strength our methodology uncovering genetic implications

Language: Английский

Citations

0
Resistance to Allosteric Inhibitors DOI
Ian R Outhwaite,

Isabelle Kwan,

Ariel Leyte-Vidal

et al.

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 169133 - 169133

Published: April 1, 2025

Citations

0
Allosteric modulation of Grb2 drives ligand-dependent signal responses DOI Creative Commons

Mariana Di Felice,

Lucrezia Romana Rolfi,

Julian Toso

et al.

Biology Direct, Journal Year: 2025, Volume and Issue: 20(1)

Published: May 23, 2025

Language: Английский

Citations

0
Pioneer in Molecular Biology: Conformational Ensembles in Molecular Recognition, Allostery, and Cell Function DOI
Ruth Nussinov

Published: Jan. 1, 2024

Language: Английский

Citations

0