Site-specific incorporation of 19F-nulcei at protein C-terminus to probe allosteric conformational transitions of metalloproteins DOI Creative Commons
X. Liu, Pengfei Guo, Qinhong Yu

и другие.

Communications Biology, Год журнала: 2024, Номер 7(1)

Опубликована: Дек. 3, 2024

Allosteric conformational change is an important paradigm in the regulation of protein function, which typically triggered by binding small cofactors, metal ions or partners. Here, we found those transitions can be effectively monitored 19F NMR, facilitated a site-specific incorporation strategy at C-terminus using asparaginyl endopeptidase (AEP). Three case studies show that C-terminal 19F-nuclei reveal dynamics not only adjacent but also distal to C-terminus, including occurring hemoprotein neuroglobin (Ngb), calmodulin (CaM), and cobalt metalloregulator (CoaR) responding both tetrapyrrole. In Ngb, heme orientation disorder affected missense mutations perturb backbone rigidity surface charges close axial ligands. CaM, ideal probe for detecting states Ca2+, peptides inhibitors. Furthermore, multiple 19F-moieties were incorporated into two domains CoaR, revealing intrinsically disordered tail might allosteric switch maintain homeostasis balance corrinoid biosynthesis. This study demonstrates AEP-based 19F-modification applied various targets regulation, especially biological processes modulated C-terminus. The labeling catalyzed OaAEP1C247A efficient approach utilize compatible with genetic code expansion technology. cases this suitable probing metalloproteins.

Язык: Английский

The Evolving T Cell Receptor Recognition Code: The Rules Are More Like Guidelines DOI Open Access

George I. Gray,

P. Chukwunalu Chukwuma,

Bassant Eldaly

и другие.

Immunological Reviews, Год журнала: 2025, Номер 329(1)

Опубликована: Янв. 1, 2025

ABSTRACT αβ T cell receptor (TCR) recognition of peptide–MHC complexes lies at the core adaptive immunity, balancing specificity and cross‐reactivity to facilitate effective antigen discrimination. Early structural studies established basic frameworks helpful for understanding contextualizing TCR features such as peptide MHC restriction. However, growing database launched from work continue reveal exceptions common assumptions simplifications derived earlier work. Here we explore our evolving recognition, illustrating how biophysical investigations regularly uncover complex phenomena that push against paradigms expand TCRs bind discriminate between peptide/MHC complexes. We discuss implications these findings basic, translational, predictive immunology, including challenges in accounting inherent adaptability, flexibility, occasional sloppiness characterize recognition.

Язык: Английский

Процитировано

1
A potential allosteric inhibitor of SARS-CoV-2 main protease (Mpro) identified through metastable state analysis DOI Creative Commons
Asma Fatima,

Anupriya M. Geethakumari,

Wesam S. Ahmed

и другие.

Frontiers in Molecular Biosciences, Год журнала: 2024, Номер 11

Опубликована: Сен. 6, 2024

Anti-COVID19 drugs, such as nirmatrelvir, have been developed targeting the SARS-CoV-2 main protease, M

Язык: Английский

Процитировано

3
Dynamic allostery in the peptide/MHC complex enables TCR neoantigen selectivity DOI Creative Commons
Jiaqi Ma, Cory M. Ayres, Chad A. Brambley

и другие.

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 20, 2025

Язык: Английский

Процитировано

0
BaNDyT: Bayesian Network Modeling of Molecular Dynamics Trajectories DOI
Elizaveta Mukhaleva, Babgen Manookian, Hanyu Chen

и другие.

Journal of Chemical Information and Modeling, Год журнала: 2025, Номер unknown

Опубликована: Янв. 23, 2025

Bayesian network modeling (BN modeling, or BNM) is an interpretable machine learning method for constructing probabilistic graphical models from the data. In recent years, it has been extensively applied to diverse types of biomedical data sets. Concurrently, our ability perform long-time scale molecular dynamics (MD) simulations on proteins and other materials increased exponentially. However, analysis MD simulation trajectories not data-driven but rather dependent user's prior knowledge systems, thus limiting scope utility simulations. Recently, we pioneered using BNM analyzing protein complexes. The resulting BN yield novel fully insights into functional importance amino acid residues that modulate proteins' function. this report, describe BaNDyT software package implements specifically attuned We believe first include specialized advanced features a model. here software's uses, methods associated with it, comprehensive Python interface underlying generalist code. This provides powerful versatile mechanism users control workflow. As application example, have utilized methodology study how membrane proteins, G protein-coupled receptors, selectively couple proteins. can be used any as well polymeric materials.

Язык: Английский

Процитировано

0
The Evolving Landscape of Protein Allostery: From Computational and Experimental Perspectives DOI

E. Srinivasan,

Grigor Arakelov, Nikolay V. Dokholyan

и другие.

Journal of Molecular Biology, Год журнала: 2025, Номер unknown, С. 169060 - 169060

Опубликована: Март 1, 2025

Язык: Английский

Процитировано

0
Computation model predicts Rho GTPase function with the Plexin Transmembrane receptor GAP activity on Rap1b via dynamic allosteric changes DOI Creative Commons
Nisha Bhattarai,

Lindsay Morrison,

Angela Gabriella Gomes

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 15, 2025

ABSTRACT Plexin-semaphorin signaling regulates key processes such as cell migration, neuronal development, angiogenesis, and immune responses. Plexins stand out because they can directly bind with both Rho- Ras-family small GTPases through their intracellular domains when these are in active, GTP-bound states. This binding occurs via regions which include a Rho-GTPase Binding Domain (RBD) GTPase Activating Protein (GAP) segment. Studies have shown that Rho Ras play vital roles plexin activation. However, the structural dynamics of plexins how conformational changes affect interactions is bound Rho-GTPases or to only one specific has remained unclear. In this study, we conducted molecular (MD) simulations on six distinct plexin-GTPase systems investigate differences conformations between Plexin-B1 three GTPases: Rap1b, Rnd1, Rac1. Our analysis revealed Rac1 more altered, compared Rnd1 depending whether plexin’s GAP domain unbound Rap1b. addition, further investigated alterations network centralities Plexin-GTPases complexes, focusing Plexin (Rap1b) (Rnd1/Rac1) versus it GTPase. study exhibits stronger stable absence while shows fewer less connections comparison. These computational models features broadly agree experimental results from hydrogen-deuterium exchange detected by mass spectrometry (HDX-MS). Such insights provide better understanding mechanisms underlying Plexin-GTPase complexities involving general.

Язык: Английский

Процитировано

0
Multiply Perturbed Response to Disclose Allosteric Control of Conformational Change: Application to Fluorescent Biosensor Design DOI
Melike Berksöz, Ali Rana Atılgan, Burak Kocuk

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 6, 2025

Abstract Proteins exhibit remarkable conformational flexibility, enabling precise functional regulation through allostery. A key application of allostery is in the design protein-based sensors, which detect environmental changes—such as ligand binding or post-translational modifications—and convert these cues into measurable signals (e.g., fluorescence). Here, we investigate a series ligand-binding proteins that serve sensing domains direct-response fluorescent biosensors, wherein enhances fluorescence output. We employ multiple force approach term Multiply Perturbed Response (MPR) to identify “hot spot” residues drive transition from an apo (inactive/OFF) holo (active/ON) state. first present two efficient computational approaches determine and forces maximize overlap observed change. then maximizer for up five insertion locations, compare them with actual sites used existing biosensors. This work utility linear response theory-based methods uncovering functionally significant regions trigger known The might prove useful not only locating allosteric sites, but may also find applications offering physics-based collective variables mapping pathways proteins.

Язык: Английский

Процитировано

0
Multiply Perturbed Response to Disclose Allosteric Control of Conformational Change: Application to Fluorescent Biosensor Design DOI
Melike Berksöz, Ali Rana Atılgan, Burak Kocuk

и другие.

Journal of Molecular Biology, Год журнала: 2025, Номер unknown, С. 169234 - 169234

Опубликована: Май 1, 2025

Язык: Английский

Процитировано

0
Exploiting allosteric modulation: a new frontier for precision medicine DOI
Esther Ugo Alum, Chidozie Dennis Udechukwu,

David Chukwu Obasi

и другие.

Molecular Biology Reports, Год журнала: 2025, Номер 52(1)

Опубликована: Июнь 4, 2025

Язык: Английский

Процитировано

0
Allostery Illuminated: Harnessing AI and Machine Learning for Drug Discovery DOI
María‐Jesús Blanco, Melissa J. Buskes, Rajiv Gandhi Govindaraj

и другие.

ACS Medicinal Chemistry Letters, Год журнала: 2024, Номер 15(9), С. 1449 - 1455

Опубликована: Авг. 30, 2024

In the past several years there has been rapid adoption of artificial intelligence (AI) and machine learning (ML) tools for drug discovery. this Microperspective, we comment on recent AI/ML applications to discovery allosteric modulators, focusing breakthroughs with AlphaFold, structure-based (SBDD), medicinal chemistry applications. We discuss how these technologies are facilitating remaining challenges identify binding sites ligands.

Язык: Английский

Процитировано

3