The probability of cryptic pocket opening controls functional tradeoffs in filovirus immune evasion. DOI Creative Commons
Upasana L. Mallimadugula, Matthew A. Cruz, Neha Vithani

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 23, 2024

Abstract Cryptic pockets are of growing interest as potential drug targets, particularly to control protein-nucleic acid interactions that often occur via flat surfaces. However, it remains unclear whether cryptic contribute protein function or if they merely happenstantial features can easily be evolved away achieve resistance. Here, we explore a pocket in the Interferon Inhibitory Domain (IID) viral 35 (VP35) Zaire ebolavirus aids its ability bind double-stranded RNA (dsRNA). We use simulations and experiments study relationship between opening dsRNA binding IIDs two other filoviruses, Reston Marburg. These homologs have nearly identical structures but block different interferon pathways due affinities for blunt ends backbone dsRNA. Simulations thiol-labeling demonstrate varying probabilities opening. Subsequent dsRNA-binding assays suggest closed conformations preferentially while open prefer backbone. Point mutations modulate proteins further confirm this preference. results has function, suggesting under selective pressure may difficult evolve

Язык: Английский

Functional dynamics of G protein-coupled receptors reveal new routes for drug discovery DOI Creative Commons
Paolo Conflitti, Edward Lyman, Mark S.P. Sansom

и другие.

Nature Reviews Drug Discovery, Год журнала: 2025, Номер unknown

Опубликована: Янв. 2, 2025

Язык: Английский

Процитировано

3
Toward physics‐based precision medicine: Exploiting protein dynamics to design new therapeutics and interpret variants DOI Creative Commons
Artur Meller,

Devin Kelly,

Louis G. Smith

и другие.

Protein Science, Год журнала: 2024, Номер 33(3)

Опубликована: Фев. 15, 2024

The goal of precision medicine is to utilize our knowledge the molecular causes disease better diagnose and treat patients. However, there a substantial mismatch between small number food drug administration (FDA)-approved drugs annotated coding variants compared needs medicine. This review introduces concept physics-based medicine, scalable framework that promises improve understanding sequence-function relationships accelerate discovery. We show accounting for ensemble structures protein adopts in solution with computer simulations overcomes many limitations imposed by assuming single structure. highlight studies dynamics recent methods analysis structural ensembles. These demonstrate differences conformational distributions predict functional within families variants. Thanks new computational tools are providing unprecedented access ensembles, this insight may enable accurate predictions variant pathogenicity entire libraries further explicitly like alchemical free energy calculations or docking Markov state models, can uncover novel lead compounds. To conclude, we cryptic pockets, cavities absent experimental structures, provide an avenue target proteins currently considered undruggable. Taken together, provides roadmap field science

Язык: Английский

Процитировано

9
SGLT2 inhibitors activate pantothenate kinase in the human heart DOI Creative Commons

Nicholas Forelli,

Deborah Eaton, Jiten Patel

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 27, 2024

Abstract Inhibitors of sodium glucose cotransporter-2 (SGLT2i) demonstrate strong symptomatic and mortality benefits in the treatment heart failure but appear to do so independently SGLT2. The relevant pharmacologic target SGLT2i remains unclear. We show here that directly activate pantothenate kinase 1 (PANK1), rate-limiting enzyme initiates conversion (vitamin B5) coenzyme-A (CoA), an obligate co-factor for all major pathways fuel use heart. Using stable-isotope infusion studies, we promote consumption, CoA synthesis, rescue decreased levels human failing hearts, broadly stimulate ex vivo perfused cardiac blocks from patients with failure. Furthermore, bind PANK1 at physiological concentrations enzymatic activity assays purified components. Novel silico dynamic modeling identified site binding on indicated a mechanism activation involving prevention allosteric inhibition by acyl-CoA species. Finally, prevents SGLT2i-mediated increased contractility isolated adult cardiomyocytes. In summary, robust specific off-target SGLT2i, promoting synthesis efficient providing likely explanation remarkable clinical SGLT2i.

Язык: Английский

Процитировано

4
Opening and closing of a cryptic pocket in VP35 toggles it between two different RNA-binding modes DOI Open Access
Upasana L. Mallimadugula, Matthew A. Cruz, Neha Vithani

и другие.

Опубликована: Янв. 3, 2025

Cryptic pockets are of growing interest as potential drug targets, particularly to control protein-nucleic acid interactions that often occur via flat surfaces. However, it remains unclear whether cryptic contribute protein function or if they merely happenstantial features can easily be evolved away achieve resistance. Here, we explore a pocket in the Interferon Inhibitory Domain (IID) viral 35 (VP35) Zaire ebolavirus aids its ability bind double-stranded RNA (dsRNA). We use simulations and experiments study relationship between opening dsRNA binding IIDs two other filoviruses, Reston Marburg. These homologs have nearly identical structures but block different interferon pathways due affinities for blunt ends backbone dsRNA. Simulations thiol-labeling demonstrate varying probabilities opening. Subsequent dsRNA-binding assays suggest closed conformations preferentially while open prefer backbone. Point mutations modulate proteins further confirm this preference. results has function, suggesting under selective pressure may difficult evolve

Язык: Английский

Процитировано

0
Opening and closing of a cryptic pocket in VP35 toggles it between two different RNA-binding modes DOI Open Access
Upasana L. Mallimadugula, Matthew A. Cruz, Neha Vithani

и другие.

Опубликована: Янв. 3, 2025

Cryptic pockets are of growing interest as potential drug targets, particularly to control protein-nucleic acid interactions that often occur via flat surfaces. However, it remains unclear whether cryptic contribute protein function or if they merely happenstantial features can easily be evolved away achieve resistance. Here, we explore a pocket in the Interferon Inhibitory Domain (IID) viral 35 (VP35) Zaire ebolavirus aids its ability bind double-stranded RNA (dsRNA). We use simulations and experiments study relationship between opening dsRNA binding IIDs two other filoviruses, Reston Marburg. These homologs have nearly identical structures but block different interferon pathways due affinities for blunt ends backbone dsRNA. Simulations thiol-labeling demonstrate varying probabilities opening. Subsequent dsRNA-binding assays suggest closed conformations preferentially while open prefer backbone. Point mutations modulate proteins further confirm this preference. results has function, suggesting under selective pressure may difficult evolve

Язык: Английский

Процитировано

0
The G protein inhibitor YM-254890 is an allosteric glue DOI Creative Commons

Tony Trent,

Justin J. Miller, Kendall Blumer

и другие.

Journal of Molecular Biology, Год журнала: 2025, Номер unknown, С. 169084 - 169084

Опубликована: Март 1, 2025

Язык: Английский

Процитировано

0
A Reversible Spherical Geometric Conversion of Protein Backbone Structure Coordinate Matrix to Three Independent Vectors of ρ, θ and φ DOI Open Access
Wei Li

Опубликована: Апрель 8, 2024

Due to the vast conformational space proteins can adopt, accurate and efficient prediction of protein structure remains still a challenging task, coupled with intricacies interatomic interactions limitations current computational models in effectively navigating this complex molecular landscape. Additionally, lack comprehensive experimental data for all structures further exacerbates difficulty reliable machine learning-based three-dimensional conformations proteios building block life. Geometrically, Cartesian coordinate system (CCS, X, Y Z) spherical (SCS, ρ, θ φ) are two interconvertible systems, like sides one coin. Since beginning Protein Data Bank (PDB) 1971, CCS has been default approach specify atomic positions Z PDB. In manuscript, therefore, I present novel method reversible geometric conversion backbone matrices three independent vectors: φ. This facilitates lossless extraction essential structural features from data, enabling development advanced algorithms future. short, inter-atomic SCS offers yet means representing geometry, leveraging coordinates capture spatial relationships compact intuitive manner, provide robust framework feature ongoing efforts advancing field prediction, holy grail biology.

Язык: Английский

Процитировано

3
The G protein inhibitor YM-254890 is an allosteric glue DOI Creative Commons

Tony Trent,

Justin J. Miller, Gregory R. Bowman

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 28, 2024

Abstract Given the prominence of G protein coupled receptors (GPCRs) as drug targets, targeting their immediate downstream effectors, proteins, could be immense therapeutic value. The discovery that natural product YM-254890 (YM) can arrest uveal melanoma by specifically inhibiting constitutively active Gq/11without impacting other families demonstrates potential this approach. However, efforts to find family-specific inhibitors have had limited success. Better understanding mechanism YM facilitate develop highly specific inhibitors. We hypothesized differences between conformational distributions various proteins play an important role in determining he specificity like YM. To explore hypothesis, we built Markov state models (MSMs) from molecular dynamics simulations Gα subunits three different predominantly contacts Gα. also modeled heterotrimeric versions these where is bound Gβγ heterodimer. YM-sensitive a higher probability adopting YM-bound-like conformations than insensitive variants. There strong allosteric coupling YM- and Gβγ-binding interfaces This allostery gives rise positive cooperativity, wherein presence enhances preorganization for binding. predict acts “allosteric” glue allosterically stabilizes complex despite minimal Gβγ.

Язык: Английский

Процитировано

1
The probability of cryptic pocket opening controls functional tradeoffs in filovirus immune evasion. DOI Creative Commons
Upasana L. Mallimadugula, Matthew A. Cruz, Neha Vithani

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 23, 2024

Abstract Cryptic pockets are of growing interest as potential drug targets, particularly to control protein-nucleic acid interactions that often occur via flat surfaces. However, it remains unclear whether cryptic contribute protein function or if they merely happenstantial features can easily be evolved away achieve resistance. Here, we explore a pocket in the Interferon Inhibitory Domain (IID) viral 35 (VP35) Zaire ebolavirus aids its ability bind double-stranded RNA (dsRNA). We use simulations and experiments study relationship between opening dsRNA binding IIDs two other filoviruses, Reston Marburg. These homologs have nearly identical structures but block different interferon pathways due affinities for blunt ends backbone dsRNA. Simulations thiol-labeling demonstrate varying probabilities opening. Subsequent dsRNA-binding assays suggest closed conformations preferentially while open prefer backbone. Point mutations modulate proteins further confirm this preference. results has function, suggesting under selective pressure may difficult evolve

Язык: Английский

Процитировано

0