* . *
  • About
  • Advertise
  • Privacy & Policy
  • Contact
Friday, June 6, 2025
Earth-News
  • Home
  • Business
  • Entertainment
    Traveling Tacos and Tequila Festival to stop at Florence Yall’s stadium this October – Cincinnati Enquirer

    Get Ready for a Flavor Fiesta: Traveling Tacos and Tequila Festival Hits Florence Y’all’s Stadium This October!

    9 things to do this weekend in Lake County plus a look ahead – Leesburg Daily Commercial

    Discover 9 Exciting Weekend Adventures in Lake County and What’s Coming Up!

    Shows to Watch – The Advocate

    Must-See Shows You Can’t Miss!

    Fox News Entertainment Newsletter: Celebrities mentioned during Diddy’s high-profile sex trafficking trial – Fox News

    Fox News Entertainment Newsletter: Celebrities mentioned during Diddy’s high-profile sex trafficking trial – Fox News

    ‘Sinners,’ starring Michael B. Jordan, is now streaming on Prime Video – About Amazon

    Experience the Thrills of ‘Sinners’ Starring Michael B. Jordan – Now Streaming on Prime Video!

    California Mid-State Fair announces entertainment lineups for Frontier and Mission stages – KSBY News

    Exciting Entertainment Lineup Unveiled for California Mid-State Fair’s Frontier and Mission Stages!

  • General
  • Health
  • News

    Cracking the Code: Why China’s Economic Challenges Aren’t Shaking Markets, Unlike America’s” – Bloomberg

    Trump’s Narrow Window to Spread the Truth About Harris

    Trump’s Narrow Window to Spread the Truth About Harris

    Israel-Gaza war live updates: Hamas leader Ismail Haniyeh assassinated in Iran, group says

    Israel-Gaza war live updates: Hamas leader Ismail Haniyeh assassinated in Iran, group says

    PAP Boss to Niger Delta Youths, Stay Away from the Protest

    PAP Boss to Niger Delta Youths, Stay Away from the Protest

    Court Restricts Protests In Lagos To Freedom, Peace Park

    Court Restricts Protests In Lagos To Freedom, Peace Park

    Fans React to Jazz Jennings’ Inspiring Weight Loss Journey

    Fans React to Jazz Jennings’ Inspiring Weight Loss Journey

    Trending Tags

    • Trump Inauguration
    • United Stated
    • White House
    • Market Stories
    • Election Results
  • Science
  • Sports
  • Technology

    Waunakee Fifth-Graders Dive into the Future at Exciting Tech Day!

    Property Technology Magazine Unveils “PropTech Top 50 Index” and the “2025 PropTech Trends Report – The Great Rebuild.” – Business Wire

    Property Technology Magazine Unveils “PropTech Top 50 Index” and the “2025 PropTech Trends Report – The Great Rebuild.” – Business Wire

    Micron Technology (NASDAQ:MU) Stock Price Expected to Rise, UBS Group Analyst Says – MarketBeat

    UBS Analyst Predicts Surge in Micron Technology Stock Price!

    Domo to Participate in the D.A. Davidson Technology Summit – Business Wire

    Domo Set to Shine at the D.A. Davidson Technology Summit!

    When fiction becomes fact: 3 pieces of modern technology inspired by Star Trek – Redshirts Always Die

    From Screen to Reality: 3 Modern Technologies Inspired by Star Trek

    The Isfahan Center for Nuclear Technology – UCF, ZPP, and IRR10 – Alma Research and Education Center

    Exploring the Isfahan Center for Nuclear Technology: Innovations and Insights from UCF, ZPP, and IRR10

    Trending Tags

    • Nintendo Switch
    • CES 2017
    • Playstation 4 Pro
    • Mark Zuckerberg
No Result
View All Result
  • Home
  • Business
  • Entertainment
    Traveling Tacos and Tequila Festival to stop at Florence Yall’s stadium this October – Cincinnati Enquirer

    Get Ready for a Flavor Fiesta: Traveling Tacos and Tequila Festival Hits Florence Y’all’s Stadium This October!

    9 things to do this weekend in Lake County plus a look ahead – Leesburg Daily Commercial

    Discover 9 Exciting Weekend Adventures in Lake County and What’s Coming Up!

    Shows to Watch – The Advocate

    Must-See Shows You Can’t Miss!

    Fox News Entertainment Newsletter: Celebrities mentioned during Diddy’s high-profile sex trafficking trial – Fox News

    Fox News Entertainment Newsletter: Celebrities mentioned during Diddy’s high-profile sex trafficking trial – Fox News

    ‘Sinners,’ starring Michael B. Jordan, is now streaming on Prime Video – About Amazon

    Experience the Thrills of ‘Sinners’ Starring Michael B. Jordan – Now Streaming on Prime Video!

    California Mid-State Fair announces entertainment lineups for Frontier and Mission stages – KSBY News

    Exciting Entertainment Lineup Unveiled for California Mid-State Fair’s Frontier and Mission Stages!

  • General
  • Health
  • News

    Cracking the Code: Why China’s Economic Challenges Aren’t Shaking Markets, Unlike America’s” – Bloomberg

    Trump’s Narrow Window to Spread the Truth About Harris

    Trump’s Narrow Window to Spread the Truth About Harris

    Israel-Gaza war live updates: Hamas leader Ismail Haniyeh assassinated in Iran, group says

    Israel-Gaza war live updates: Hamas leader Ismail Haniyeh assassinated in Iran, group says

    PAP Boss to Niger Delta Youths, Stay Away from the Protest

    PAP Boss to Niger Delta Youths, Stay Away from the Protest

    Court Restricts Protests In Lagos To Freedom, Peace Park

    Court Restricts Protests In Lagos To Freedom, Peace Park

    Fans React to Jazz Jennings’ Inspiring Weight Loss Journey

    Fans React to Jazz Jennings’ Inspiring Weight Loss Journey

    Trending Tags

    • Trump Inauguration
    • United Stated
    • White House
    • Market Stories
    • Election Results
  • Science
  • Sports
  • Technology

    Waunakee Fifth-Graders Dive into the Future at Exciting Tech Day!

    Property Technology Magazine Unveils “PropTech Top 50 Index” and the “2025 PropTech Trends Report – The Great Rebuild.” – Business Wire

    Property Technology Magazine Unveils “PropTech Top 50 Index” and the “2025 PropTech Trends Report – The Great Rebuild.” – Business Wire

    Micron Technology (NASDAQ:MU) Stock Price Expected to Rise, UBS Group Analyst Says – MarketBeat

    UBS Analyst Predicts Surge in Micron Technology Stock Price!

    Domo to Participate in the D.A. Davidson Technology Summit – Business Wire

    Domo Set to Shine at the D.A. Davidson Technology Summit!

    When fiction becomes fact: 3 pieces of modern technology inspired by Star Trek – Redshirts Always Die

    From Screen to Reality: 3 Modern Technologies Inspired by Star Trek

    The Isfahan Center for Nuclear Technology – UCF, ZPP, and IRR10 – Alma Research and Education Center

    Exploring the Isfahan Center for Nuclear Technology: Innovations and Insights from UCF, ZPP, and IRR10

    Trending Tags

    • Nintendo Switch
    • CES 2017
    • Playstation 4 Pro
    • Mark Zuckerberg
No Result
View All Result
Earth-News
No Result
View All Result
Home Science

The GPCR Puzzle: New Research Reveals Molecular Origins of Function for a Key Drug Target

February 17, 2024
in Science
The GPCR Puzzle: New Research Reveals Molecular Origins of Function for a Key Drug Target
Share on FacebookShare on Twitter

By St. Jude Children’s Research Hospital February 17, 2024

GPCR Structure

By looking at each individual component of the β2 adrenergic receptor and seeing how they contribute to the overall function of the protein, researchers from St. Jude along with international collaborators are able to view the network that allows ligand binding to be translated across the membrane to within the cell. Artwork by Zhaowen Luo. Credit: St. Jude Children’s Research Hospital

Scientists at St. Jude Children’s Research Hospital, collaborating internationally, used data science, pharmacology, and structural details to explore at the atomic level how each amino acid in the adrenaline-binding receptor affects its activity when interacting with this natural ligand.

They discovered precisely which amino acids control the key pharmacological properties of the ligand. The adrenaline receptor studied is a member of the G protein-coupled receptor (GPCR) family, and this family is the target of one-third of all Food and Drug Administration (FDA)-approved drugs. Thus, understanding how GPCRs respond to natural or therapeutic ligands is critical for developing new therapies with precise effects on receptor activity. The work was published today in Science.

To understand how a watch works, one might take it apart, piece by piece, and study the role played by each component in its timekeeping function. Similarly, in a protein such as a GPCR, each amino acid might play a different role in how the protein responds to an external signal. Researchers at St. Jude, in collaboration with scientists from Stanford University, the University of Montreal, the MRC Laboratory of Molecular Biology, and Cambridge University, investigated the β2-adrenergic receptor (β2AR) by substituting one amino acid at a time to understand the contribution of each amino acid in this receptor to mediate a signaling response.

“Scientists learn how genes contribute to cell function by disrupting them one at a time. We asked, ‘Why don’t we take this one level deeper? Let’s understand how every amino acid contributes to the functioning of a receptor by mutating them, one amino acid at a time,’” said co-corresponding author M. Madan Babu, Ph.D., from St. Jude’s Department of Structural Biology, Center of Excellence for Data-Driven Discovery director and the George J. Pedersen Endowed Chair in Biological Data Science. “Through evolution, every amino acid in the receptor has been sculpted in some way or another to ensure that it binds the natural ligand, in this case adrenaline, and elicits the appropriate physiological response.”

Finding function in the form

GPCRs are proteins that span the cell’s membrane and connect the outside of the cell to its internal environment by transmitting external signals to the inside of the cell. In the case of the β2AR, adrenaline binds to the GPCR on the part outside of the cell, inducing a response inside the cell.

When a ligand binds, it causes changes in the shape of the receptor, especially in the intracellular region of the receptor where a G protein binds. The binding sites for the ligand and the G protein are on opposite sides of the protein but connect through a complex network of amino acid contacts that span the entire protein. Conformational (shape) changes within the GPCR activate the G protein to trigger a downstream signaling response within the cell. Through effects on multiple tissues and GPCRs, including the β2AR, adrenaline can trigger the fight-or-flight response, such as during an adrenaline surge.

To understand the role of each amino acid in a GPCR, Franziska Heydenreich, Ph.D., now of the Philipps University of Marburg, the lead and co-corresponding author of this project, mutated each of the 412 amino acids in the β2AR. She then evaluated each mutant’s response to the ligand adrenaline and determined the classical pharmacological properties of efficacy and potency. Efficacy measures the maximum response a ligand can elicit, and potency measures the amount of ligand required to elicit half of the maximum response. The aim was to reveal, on an atomic scale, how each amino acid contributes to these pharmacological properties.

“Surprisingly, only about 80 of the more than 400 amino acids contributed to these pharmacological properties. Of these pharmacologically relevant amino acids, only one-third were located within regions where the ligand or G protein bound to the receptor,” Heydenreich said.

“It was fascinating to observe that there are some amino acids that control efficacy, some that control potency and then there are others that affect both,” Babu said. “It means if you want to make a more potent or efficacious drug, you now know there are specific residues that the new ligand needs to influence.” The researchers also noted that the individual contribution of each residue to efficacy and potency was not equal, implying even more opportunities for fine-tuning drug responses while designing new therapeutic ligands.

“Efficacy and potency have been measured for numerous ligand-receptor signaling systems for several decades. Now we can understand how specific amino acids in a protein’s sequence can influence these pharmacological properties,” Babu explained.

“A fascinating aspect of the results is that potency and efficacy can be regulated independently of each other through distinct mechanisms. This provides a basis for understanding how genetic variation influences drug responses among individuals,” Michel Bouvier, PhD, co-corresponding author from the Department of Biochemistry and Molecular Medicine and General Director of the Institute for Research in Immunology and Cancer of the University of Montreal added.

A beautiful network

Prior research illustrated the structure of both the active and inactive states of the β2AR. Building on this knowledge, the researchers embarked on a new investigation. They explored whether the two-thirds of pharmacologically relevant amino acids previously demonstrated to be not involved in ligand or G-protein binding might play a role in the transition between the active and inactive states of the receptor.

“We systematically started looking at every residue contact unique to the active state,” Heydenreich said, “to understand whether all the amino acids that make an active-state contact are important.”

The researchers developed a data science framework to integrate pharmacological and structural data systematically and revealed the first comprehensive picture of GPCR signaling. “When we mapped the pharmacological data onto the structure, they formed a beautiful network,” said Babu.

“It provided new insights into the allosteric network linking the ligand binding pocket to the G protein binding site that governs efficacy and potency.” Added Brian Kobilka, co-corresponding author and the 2012 Nobel Prize winner in Chemistry from Stanford University School of Medicine.

By understanding GPCR signaling at the atomic level, the researchers are optimistic that they can begin probing even deeper — to see the transient sub-states between the active and inactive conformations and to explore the conformational landscape of proteins.

“We now know which mutants to go after, those that only affect efficacy, potency, or both,” Heydenreich said.

“Now, we can perform molecular dynamics calculations and single-molecule experiments on those mutants to reveal the exact mechanisms by which the allosteric network influences efficacy and potency to mediate a signaling response. This is a direction we are pursuing through a St. Jude Research Collaborative on GPCRs that includes PIs from several institutions.” Babu explained.

Apart from these “driver” residues that are involved in mediating active state-specific contacts and affect pharmacology when mutated, Babu and his colleagues intend to probe other key findings revealed by this work. They aim to study “passenger” amino acids that, despite making contacts in the active state, do not affect efficacy or potency when mutated. They are also interested in “modulator” residues that don’t mediate active state-specific contacts but alter pharmacology when mutated. Their data science approach, integrating structural information and pharmacological measurements, isn’t limited to the β2AR. It can be extended to any GPCR to enhance our understanding of the mechanics governing this crucial class of drug targets.

Reference: “Molecular determinants of ligand efficacy and potency in GPCR signaling” by Franziska M. Heydenreich, Maria Marti-Solano, Manbir Sandhu, Brian K. Kobilka, Michel Bouvier and M. Madan Babu, 22 December 2023, Science.
DOI: 10.1126/science.adh1859

The study’s other authors include Maria Marti-Solano, University of Cambridge, and Manbir Sandhu, St. Jude.

The study was supported by grants from Marie Skłodowska-Curie Individual Fellowships from the European Union’s Horizon 2020 research (844622, 832620), the American Heart Association (19POST34380839), the National Institutes of Health (R01NS028471), the Canadian Institute of Health Research (FDN#148431), the UK Medical Research Council (MC_U105185859), the Royal Society University (URFR1221205), the Isaac Newton Trust [22.23(d)], the Wellcome Trust Institutional Strategic Support Fund, and ALSAC, the fundraising and awareness organization of St. Jude.

>>> Read full article>>>
Copyright for syndicated content belongs to the linked Source : SciTechDaily – https://scitechdaily.com/the-gpcr-puzzle-new-research-reveals-molecular-origins-of-function-for-a-key-drug-target/

Tags: PuzzleResearchscience
Previous Post

Unlocking the Secrets of Bone Loss in Zero Gravity

Next Post

Atomic Freeze-Frame: Electron Motion in Water Captured For First Time

‘Elon is going to get decimated:’ How Trump’s feud with the world’s richest man might end – USA Today

Elon vs. Trump: The Epic Showdown That Could Change Everything!

June 6, 2025
Trump’s Tariffs Expected to Drag Down the Global Economy – The New York Times

Trump’s Tariffs: A Looming Threat to the Global Economy

June 6, 2025
Traveling Tacos and Tequila Festival to stop at Florence Yall’s stadium this October – Cincinnati Enquirer

Get Ready for a Flavor Fiesta: Traveling Tacos and Tequila Festival Hits Florence Y’all’s Stadium This October!

June 6, 2025
Champaign-based Health Alliance plans to end all coverage, eliminating more than 600 jobs – WGLT

Health Alliance in Champaign to Cut All Coverage, Impacting Over 600 Jobs

June 6, 2025
Book Review: ‘Buckley,’ by Sam Tanenhaus – The New York Times

Book Review: ‘Buckley,’ by Sam Tanenhaus – The New York Times

June 6, 2025

Waunakee Fifth-Graders Dive into the Future at Exciting Tech Day!

June 6, 2025
Kenton Ridge wins 1st state high school championship – Yahoo Sports

Kenton Ridge Claims Historic First State High School Championship!

June 6, 2025
Ecological Restoration Service Market to Reach USD 87.9 Bn by 2031, Growing at 9.4% CAGR – openPR.com

Ecological Restoration Service Market Set to Soar to $87.9 Billion by 2031 with a Robust 9.4% Growth Rate!

June 6, 2025
Boise State moves forward with plans for new science building, signaling an investment in STEM majors – The Arbiter | Boise State

Boise State Unveils Ambitious Plans for Cutting-Edge Science Building, Boosting STEM Education!

June 6, 2025
The Science Of De-Extinction Is Providing Hope For Nature’s Future – Forbes

Reviving the Past: How De-Extinction Science Offers New Hope for Our Planet’s Future

June 6, 2025

Categories

Archives

June 2025
MTWTFSS
 1
2345678
9101112131415
16171819202122
23242526272829
30 
« May    
Earth-News.info

The Earth News is an independent English-language daily published Website from all around the World News

Browse by Category

  • Business (20,132)
  • Ecology (670)
  • Economy (685)
  • Entertainment (21,591)
  • General (15,267)
  • Health (9,726)
  • Lifestyle (687)
  • News (22,149)
  • People (685)
  • Politics (692)
  • Science (15,902)
  • Sports (21,188)
  • Technology (15,670)
  • World (670)

Recent News

‘Elon is going to get decimated:’ How Trump’s feud with the world’s richest man might end – USA Today

Elon vs. Trump: The Epic Showdown That Could Change Everything!

June 6, 2025
Trump’s Tariffs Expected to Drag Down the Global Economy – The New York Times

Trump’s Tariffs: A Looming Threat to the Global Economy

June 6, 2025
  • About
  • Advertise
  • Privacy & Policy
  • Contact

© 2023 earth-news.info

No Result
View All Result

© 2023 earth-news.info

No Result
View All Result

© 2023 earth-news.info

Go to mobile version