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  1. Article ; Online: Author Correction: PRESTO-Tango as an open-source resource for interrogation of the druggable human GPCRome.

    Kroeze, Wesley K / Sassano, Maria F / Huang, Xi-Ping / Lansu, Katherine / McCorvy, John D / Giguère, Patrick M / Sciaky, Noah / Roth, Bryan L

    Nature structural & molecular biology

    2024  Volume 31, Issue 3, Page(s) 578

    Language English
    Publishing date 2024-03-14
    Publishing country United States
    Document type Published Erratum
    ZDB-ID 2126708-X
    ISSN 1545-9985 ; 1545-9993
    ISSN (online) 1545-9985
    ISSN 1545-9993
    DOI 10.1038/s41594-023-01129-x
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  2. Article: Molecular basis of proton-sensing by G protein-coupled receptors.

    Howard, Matthew K / Hoppe, Nicholas / Huang, Xi-Ping / Macdonald, Christian B / Mehrota, Eshan / Rockefeller Grimes, Patrick / Zahm, Adam / Trinidad, Donovan D / English, Justin / Coyote-Maestas, Willow / Manglik, Aashish

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Three proton-sensing G protein-coupled receptors (GPCRs), GPR4, GPR65, and GPR68, respond to changes in extracellular pH to regulate diverse physiology and are implicated in a wide range of diseases. A central challenge in determining how protons ... ...

    Abstract Three proton-sensing G protein-coupled receptors (GPCRs), GPR4, GPR65, and GPR68, respond to changes in extracellular pH to regulate diverse physiology and are implicated in a wide range of diseases. A central challenge in determining how protons activate these receptors is identifying the set of residues that bind protons. Here, we determine structures of each receptor to understand the spatial arrangement of putative proton sensing residues in the active state. With a newly developed deep mutational scanning approach, we determined the functional importance of every residue in proton activation for GPR68 by generating ∼9,500 mutants and measuring effects on signaling and surface expression. This unbiased screen revealed that, unlike other proton-sensitive cell surface channels and receptors, no single site is critical for proton recognition in GPR68. Instead, a network of titratable residues extend from the extracellular surface to the transmembrane region and converge on canonical class A GPCR activation motifs to activate proton-sensing GPCRs. More broadly, our approach integrating structure and unbiased functional interrogation defines a new framework for understanding the rich complexity of GPCR signaling.
    One-sentence summary: The protonation networks governing activation of human pH-sensing GPCRs are uncovered by integrative cryo-EM and deep mutational scanning.
    Language English
    Publishing date 2024-04-18
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.04.17.590000
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Molecular basis for selective activation of DREADD-based chemogenetics.

    Zhang, Shicheng / Gumpper, Ryan H / Huang, Xi-Ping / Liu, Yongfeng / Krumm, Brian E / Cao, Can / Fay, Jonathan F / Roth, Bryan L

    Nature

    2022  Volume 612, Issue 7939, Page(s) 354–362

    Abstract: Designer receptors exclusively activated by designer drugs (DREADDs) represent a powerful chemogenetic technology for the remote control of neuronal activity and cellular ... ...

    Abstract Designer receptors exclusively activated by designer drugs (DREADDs) represent a powerful chemogenetic technology for the remote control of neuronal activity and cellular signalling
    MeSH term(s) Neurosciences
    Chemical Substances deschloroclozapine
    Language English
    Publishing date 2022-11-30
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/s41586-022-05489-0
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  4. Article: Differential Roles of Extracellular Histidine Residues of GPR68 for Proton-Sensing and Allosteric Modulation by Divalent Metal Ions

    Huang, Xi-Ping / Kenakin, Terrence P / Gu, Shuo / Shoichet, Brian K / Roth, Bryan L

    Biochemistry. 2020 Aug. 31, v. 59, no. 38

    2020  

    Abstract: GPR68, an orphan G-protein coupled receptor, senses protons, couples to multiple G-proteins, and is also activated or inhibited by divalent metal ions. It has seven extracellular histidine residues, although it is not clear how these histidine residues ... ...

    Abstract GPR68, an orphan G-protein coupled receptor, senses protons, couples to multiple G-proteins, and is also activated or inhibited by divalent metal ions. It has seven extracellular histidine residues, although it is not clear how these histidine residues play a role in both proton-sensing and metal ion modulation. Here we demonstrate that divalent metal ions are allosteric modulators that can activate or inhibit proton activity in a concentration- and pH-dependent manner. We then show that single histidine mutants have differential and varying degrees of effects on proton-sensing and metal ion modulation. Some histidine residues play dual roles in proton-sensing and metal ion modulation, while others are important in one or the other but not both. Two extracellular disulfide bonds are predicted to constrain histidine residues to be spatially close to each other. Combining histidine mutations leads to reduced proton activity and resistance to metal ion modulation, while breaking the less conserved disulfide bond results in a more severe reduction in proton-sensing over metal modulation. The small-molecule positive allosteric modulators (PAMs) ogerin and lorazepam are not affected by these mutations and remain active at mutants with severely reduced proton activity or are resistant to metal ion modulation. These results suggest GPR68 possesses two independent allosteric modulation systems, one through interaction with divalent metal ions at the extracellular surface and another through small-molecule PAMs in the transmembrane domains. A new GPR68 model is developed to accommodate the findings which could serve as a template for further studies and ligand discovery by virtual ligand docking.
    Keywords G-protein coupled receptors ; G-proteins ; disulfide bonds ; divalent metals ; histidine ; ligands ; metal ions ; models ; mutants ; mutation ; pH ; protons
    Language English
    Dates of publication 2020-0831
    Size p. 3594-3614.
    Publishing place American Chemical Society
    Document type Article
    Note NAL-light
    ZDB-ID 1108-3
    ISSN 1520-4995 ; 0006-2960
    ISSN (online) 1520-4995
    ISSN 0006-2960
    DOI 10.1021/acs.biochem.0c00576
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  5. Article: β-Fluorofentanyls Are pH-Sensitive Mu Opioid Receptor Agonists.

    Rosas, Ricardo / Huang, Xi-Ping / Roth, Bryan L / Dockendorff, Chris

    ACS medicinal chemistry letters

    2019  Volume 10, Issue 9, Page(s) 1353–1356

    Abstract: The concept recently postulated by Stein and co-workers ( ...

    Abstract The concept recently postulated by Stein and co-workers (
    Language English
    Publishing date 2019-08-13
    Publishing country United States
    Document type Journal Article
    ISSN 1948-5875
    ISSN 1948-5875
    DOI 10.1021/acsmedchemlett.9b00335
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Differential Roles of Extracellular Histidine Residues of GPR68 for Proton-Sensing and Allosteric Modulation by Divalent Metal Ions.

    Huang, Xi-Ping / Kenakin, Terrence P / Gu, Shuo / Shoichet, Brian K / Roth, Bryan L

    Biochemistry

    2020  Volume 59, Issue 38, Page(s) 3594–3614

    Abstract: GPR68, an orphan G-protein coupled receptor, senses protons, couples to multiple G-proteins, and is also activated or inhibited by divalent metal ions. It has seven extracellular histidine residues, although it is not clear how these histidine residues ... ...

    Abstract GPR68, an orphan G-protein coupled receptor, senses protons, couples to multiple G-proteins, and is also activated or inhibited by divalent metal ions. It has seven extracellular histidine residues, although it is not clear how these histidine residues play a role in both proton-sensing and metal ion modulation. Here we demonstrate that divalent metal ions are allosteric modulators that can activate or inhibit proton activity in a concentration- and pH-dependent manner. We then show that single histidine mutants have differential and varying degrees of effects on proton-sensing and metal ion modulation. Some histidine residues play dual roles in proton-sensing and metal ion modulation, while others are important in one or the other but not both. Two extracellular disulfide bonds are predicted to constrain histidine residues to be spatially close to each other. Combining histidine mutations leads to reduced proton activity and resistance to metal ion modulation, while breaking the less conserved disulfide bond results in a more severe reduction in proton-sensing over metal modulation. The small-molecule positive allosteric modulators (PAMs) ogerin and lorazepam are not affected by these mutations and remain active at mutants with severely reduced proton activity or are resistant to metal ion modulation. These results suggest GPR68 possesses two independent allosteric modulation systems, one through interaction with divalent metal ions at the extracellular surface and another through small-molecule PAMs in the transmembrane domains. A new GPR68 model is developed to accommodate the findings which could serve as a template for further studies and ligand discovery by virtual ligand docking.
    MeSH term(s) Allosteric Regulation/drug effects ; Amino Acid Sequence ; Calcium/pharmacology ; HEK293 Cells ; Histidine/chemistry ; Humans ; Hydrogen-Ion Concentration ; Magnesium/pharmacology ; Metals, Heavy/pharmacology ; Mutation ; Protons ; Receptors, G-Protein-Coupled/chemistry ; Receptors, G-Protein-Coupled/genetics ; Receptors, G-Protein-Coupled/metabolism
    Chemical Substances GPR68 protein, human ; Metals, Heavy ; Protons ; Receptors, G-Protein-Coupled ; Histidine (4QD397987E) ; Magnesium (I38ZP9992A) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2020-09-10
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1108-3
    ISSN 1520-4995 ; 0006-2960
    ISSN (online) 1520-4995
    ISSN 0006-2960
    DOI 10.1021/acs.biochem.0c00576
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 217: Show issues Location:
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  7. Article: De Novo Design of κ-Opioid Receptor Antagonists Using a Generative Deep Learning Framework.

    Salas-Estrada, Leslie / Provasi, Davide / Qui, Xing / Kaniskan, H Ümit / Huang, Xi-Ping / DiBerto, Jeffrey F / Ribeiro, João Marcelo Lamim / Jin, Jian / Roth, Bryan L / Filizola, Marta

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Likely effective pharmacological interventions for the treatment of opioid addiction include attempts to attenuate brain reward deficits during periods of abstinence. Pharmacological blockade of the κ-opioid receptor (KOR) has been shown to abolish brain ...

    Abstract Likely effective pharmacological interventions for the treatment of opioid addiction include attempts to attenuate brain reward deficits during periods of abstinence. Pharmacological blockade of the κ-opioid receptor (KOR) has been shown to abolish brain reward deficits in rodents during withdrawal, as well as to reduce the escalation of opioid use in rats with extended access to opioids. Although KOR antagonists represent promising candidates for the treatment of opioid addiction, very few potent selective KOR antagonists are known to date and most of them exhibit significant safety concerns. Here, we used a generative deep learning framework for the
    Language English
    Publishing date 2023-04-26
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.04.25.537995
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: De Novo Design of κ-Opioid Receptor Antagonists Using a Generative Deep-Learning Framework.

    Salas-Estrada, Leslie / Provasi, Davide / Qiu, Xing / Kaniskan, Husnu Ümit / Huang, Xi-Ping / DiBerto, Jeffrey F / Lamim Ribeiro, João Marcelo / Jin, Jian / Roth, Bryan L / Filizola, Marta

    Journal of chemical information and modeling

    2023  Volume 63, Issue 16, Page(s) 5056–5065

    Abstract: Likely effective pharmacological interventions for the treatment of opioid addiction include attempts to attenuate brain reward deficits during periods of abstinence. Pharmacological blockade of the κ-opioid receptor (KOR) has been shown to abolish brain ...

    Abstract Likely effective pharmacological interventions for the treatment of opioid addiction include attempts to attenuate brain reward deficits during periods of abstinence. Pharmacological blockade of the κ-opioid receptor (KOR) has been shown to abolish brain reward deficits in rodents during withdrawal, as well as to reduce the escalation of opioid use in rats with extended access to opioids. Although KOR antagonists represent promising candidates for the treatment of opioid addiction, very few potent selective KOR antagonists are known to date and most of them exhibit significant safety concerns. Here, we used a generative deep-learning framework for the
    MeSH term(s) Rats ; Animals ; Receptors, Opioid, kappa/metabolism ; Narcotic Antagonists/pharmacology ; Deep Learning ; Analgesics, Opioid/pharmacology ; Opioid-Related Disorders
    Chemical Substances Receptors, Opioid, kappa ; Narcotic Antagonists ; Analgesics, Opioid
    Language English
    Publishing date 2023-08-09
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 190019-5
    ISSN 1549-960X ; 0095-2338
    ISSN (online) 1549-960X
    ISSN 0095-2338
    DOI 10.1021/acs.jcim.3c00651
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  9. Article ; Online: Structural insights into angiotensin receptor signaling modulation by balanced and biased agonists.

    Zhang, Dongqi / Liu, Yongfeng / Zaidi, Saheem A / Xu, Lingyi / Zhan, Yuting / Chen, Anqi / Guo, Jiangtao / Huang, Xi-Ping / Roth, Bryan L / Katritch, Vsevolod / Cherezov, Vadim / Zhang, Haitao

    The EMBO journal

    2023  Volume 42, Issue 11, Page(s) e112940

    Abstract: The peptide hormone angiotensin II regulates blood pressure mainly through the type 1 angiotensin II receptor ... ...

    Abstract The peptide hormone angiotensin II regulates blood pressure mainly through the type 1 angiotensin II receptor AT
    MeSH term(s) Humans ; Cryoelectron Microscopy ; Signal Transduction/physiology ; beta-Arrestins/metabolism ; Angiotensin II/chemistry ; Angiotensin II/metabolism ; Angiotensin II/pharmacology ; Receptors, Angiotensin/metabolism
    Chemical Substances beta-Arrestins ; Angiotensin II (11128-99-7) ; Receptors, Angiotensin
    Language English
    Publishing date 2023-04-11
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 586044-1
    ISSN 1460-2075 ; 0261-4189
    ISSN (online) 1460-2075
    ISSN 0261-4189
    DOI 10.15252/embj.2022112940
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  10. Article ; Online: Allostery of atypical modulators at oligomeric G protein-coupled receptors.

    Shivnaraine, Rabindra V / Kelly, Brendan / Elmslie, Gwendolynne / Huang, Xi-Ping / Dong, Yue John / Seidenberg, Margaret / Wells, James W / Ellis, John

    Scientific reports

    2021  Volume 11, Issue 1, Page(s) 9265

    Abstract: Many G protein-coupled receptors (GPCRs) are therapeutic targets, with most drugs acting at the orthosteric site. Some GPCRs also possess allosteric sites, which have become a focus of drug discovery. In the ... ...

    Abstract Many G protein-coupled receptors (GPCRs) are therapeutic targets, with most drugs acting at the orthosteric site. Some GPCRs also possess allosteric sites, which have become a focus of drug discovery. In the M
    MeSH term(s) Allosteric Regulation ; Allosteric Site ; Animals ; CHO Cells ; Cricetinae ; Cricetulus ; Ligands ; Molecular Dynamics Simulation ; Receptor, Muscarinic M2/chemistry ; Receptor, Muscarinic M2/genetics ; Receptor, Muscarinic M2/metabolism ; Tacrine/pharmacology
    Chemical Substances Ligands ; Receptor, Muscarinic M2 ; Tacrine (4VX7YNB537)
    Language English
    Publishing date 2021-04-29
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-021-88399-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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