Sep 2026· Proceedings of the National Academy of Sciences of the United States of America· Vol 123· 0 citations· 39 references
Medicine
TL;DR
It is shown that ligand binding reshapes a distributed network of coupled interactions that spans the active site, interdomain linker, and domain interfaces, driving domain closure, and independent perturbations converge on the same network, demonstrating that it reflects intrinsic features of the protein energy landscape.
Abstract
Significance Allosteric regulation enables proteins to transmit signals over long distances, but the mechanisms linking local ligand binding to global conformational changes remain difficult to resolve. Here, we combine NMR-based chemical shift covariance analysis with computational contact-response analysis to map the allosteric network of a large multidomain enzyme, bacterial Enzyme I. We show that ligand binding reshapes a distributed network of coupled interactions that spans the active site, interdomain linker, and domain interfaces, driving domain closure. Remarkably, independent perturbations (mutations and temperature) converge on the same network, demonstrating that it reflects intrinsic features of the protein energy landscape. This integrated approach provides a general strategy for resolving allosteric mechanisms in complex biological systems.
The SARS-CoV-2 main protease (MPro) is an essential enzyme for viral replication and a primary target for antiviral drug development. Despite extensive structural and biochemical characterization, the allosteric mechanisms by which dimerization informs conformational changes at active site lack an explicit comparison a...
Javier O. Sanlley Hernandez, Carla Calvó-Tusell, Fiona L. Kearns et al.· Biophysical Journal· 0 citations
The SARS-CoV-2 main protease (Mpro) is an essential viral enzyme whose catalytic activity strictly depends on dimerization and inter-protomer functional communication. While hundreds of symmetrical ligand-free or fully occupied structures are available, the structural and dynamical mechanisms governing asymmetric long-...
Roberto Battistutta, Luka Nikolic, Gabriele Giachin· International Journal of Bio...· 0 citations
Dynamical network analysis is used to identify key residues involved in a dynamic allostery between the N- and C-lobes that connects the major functional units of the MAP kinase p38α, providing mechanistic insight into p38α allostery and suggesting viable opportunities for the rational design of allosteric modulators o...
Suchandra Roy Acharyya, J. Weisner, Rafael C. Bernardi et al.· Nature Communications· 0 citations
This work stabilizes the crucial half-bound intermediate of a cooperative dimer in the enzyme chorismate mutase by chemically linking one NMR-visible subunit to one that cannot bind ligand, letting us watch each subunit independently.
P. J. Sapienza, T. Mileur, M. S. Khan et al.· bioRxiv· 0 citations
A two-layer regulatory mechanism in which phosphorylation rewires IDR electrostatics while pocket-binding ligands redirect folded-domain interactions is revealed, suggesting a strategy for modulating multidomain condensates through ligand-induced contact-network remodeling.
The enzyme turnover number (kcat) defines catalytic efficiency and constrains quantitative models of metabolism, yet the molecular determinants governing kcat and its response to mutation remain poorly understood. Measurements are sparse and labor-intensive, and most computational approaches provide numerical predictio...
Wei-Ren Zhao, Takeyuki Tamura· 0 citations
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