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  1. Article ; Online: Conformational insight into multi-protein signaling assemblies by hydrogen-deuterium exchange mass spectrometry.

    Harrison, Rane A / Engen, John R

    Current opinion in structural biology

    2016  Volume 41, Page(s) 187–193

    Abstract: Hydrogen-deuterium exchange (HDX) mass spectrometry (MS) can provide information about proteins that can be challenging to obtain by other means. Structure/function relationships, binding interactions, and the effects of modification have all been ... ...

    Abstract Hydrogen-deuterium exchange (HDX) mass spectrometry (MS) can provide information about proteins that can be challenging to obtain by other means. Structure/function relationships, binding interactions, and the effects of modification have all been measured with HDX MS for a diverse and growing array of signaling proteins and multiprotein signaling complexes. As a result of hardware and software improvements, receptors and complexes involved in cellular signaling-including those associated with membranes-can now be studied. The growing body of HDX MS studies of signaling complexes at membranes is particularly exciting. Recent examples are presented to illustrate what can be learned about signaling proteins with this technique.
    Language English
    Publishing date 2016-12
    Publishing country England
    Document type Review ; Journal Article
    ZDB-ID 1068353-7
    ISSN 1879-033X ; 0959-440X
    ISSN (online) 1879-033X
    ISSN 0959-440X
    DOI 10.1016/j.sbi.2016.08.003
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3206: Show issues Location:
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  2. Article ; Online: KRAS G12C Drug Development: Discrimination between Switch II Pocket Configurations Using Hydrogen/Deuterium-Exchange Mass Spectrometry.

    Lu, Jia / Harrison, Rane A / Li, Lianbo / Zeng, Mei / Gondi, Sudershan / Scott, David / Gray, Nathanael S / Engen, John R / Westover, Kenneth D

    Structure (London, England : 1993)

    2017  Volume 25, Issue 9, Page(s) 1442–1448.e3

    Abstract: KRAS G12C, the most common RAS mutation found in non-small-cell lung cancer, has been the subject of multiple recent covalent small-molecule inhibitor campaigns including efforts directed at the guanine nucleotide pocket and separate work focused on an ... ...

    Abstract KRAS G12C, the most common RAS mutation found in non-small-cell lung cancer, has been the subject of multiple recent covalent small-molecule inhibitor campaigns including efforts directed at the guanine nucleotide pocket and separate work focused on an inducible pocket adjacent to the switch motifs. Multiple conformations of switch II have been observed, suggesting that switch II pocket (SIIP) binders may be capable of engaging a range of KRAS conformations. Here we report the use of hydrogen/deuterium-exchange mass spectrometry (HDX MS) to discriminate between conformations of switch II induced by two chemical classes of SIIP binders. We investigated the structural basis for differences in HDX MS using X-ray crystallography and discovered a new SIIP configuration in response to binding of a quinazoline chemotype. These results have implications for structure-guided drug design targeting the RAS SIIP.
    MeSH term(s) Cell Line ; Crystallography, X-Ray ; Deuterium Exchange Measurement ; Drug Design ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Humans ; Mass Spectrometry ; Models, Molecular ; Molecular Conformation ; Mutation ; Proto-Oncogene Proteins p21(ras)/chemistry ; Proto-Oncogene Proteins p21(ras)/genetics ; Quinazolines/chemistry ; Quinazolines/pharmacology ; Structure-Activity Relationship
    Chemical Substances Enzyme Inhibitors ; KRAS protein, human ; Quinazolines ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)
    Language English
    Publishing date 2017-08-03
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
    ZDB-ID 1213087-4
    ISSN 1878-4186 ; 0969-2126
    ISSN (online) 1878-4186
    ISSN 0969-2126
    DOI 10.1016/j.str.2017.07.003
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    Zs.A 4141: Show issues Location:
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  3. Article ; Online: Structural Dynamics in Ras and Related Proteins upon Nucleotide Switching.

    Harrison, Rane A / Lu, Jia / Carrasco, Martin / Hunter, John / Manandhar, Anuj / Gondi, Sudershan / Westover, Kenneth D / Engen, John R

    Journal of molecular biology

    2016  Volume 428, Issue 23, Page(s) 4723–4735

    Abstract: Structural dynamics of Ras proteins contributes to their activity in signal transduction cascades. Directly targeting Ras proteins with small molecules may rely on the movement of a conserved structural motif, switch II. To understand Ras signaling and ... ...

    Abstract Structural dynamics of Ras proteins contributes to their activity in signal transduction cascades. Directly targeting Ras proteins with small molecules may rely on the movement of a conserved structural motif, switch II. To understand Ras signaling and advance Ras-targeting strategies, experimental methods to measure Ras dynamics are required. Here, we demonstrate the utility of hydrogen-deuterium exchange (HDX) mass spectrometry (MS) to measure Ras dynamics by studying representatives from two branches of the Ras superfamily, Ras and Rho. A comparison of differential deuterium exchange between active (GMPPNP-bound) and inactive (GDP-bound) proteins revealed differences between the families, with the most notable differences occurring in the phosphate-binding loop and switch II. The P-loop exchange signature correlated with switch II dynamics observed in molecular dynamics simulations focused on measuring main-chain movement. HDX provides a means of evaluating Ras protein dynamics, which may be useful for understanding the mechanisms of Ras signaling, including activated signaling of pathologic mutants, and for targeting strategies that rely on protein dynamics.
    MeSH term(s) Animals ; Humans ; Mass Spectrometry ; Molecular Dynamics Simulation ; Nucleotides/metabolism ; ras Proteins/chemistry ; ras Proteins/metabolism ; rho GTP-Binding Proteins/chemistry ; rho GTP-Binding Proteins/metabolism
    Chemical Substances Nucleotides ; ras Proteins (EC 3.6.5.2) ; rho GTP-Binding Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2016-11-20
    Publishing country England
    Document type Journal Article
    ZDB-ID 80229-3
    ISSN 1089-8638 ; 0022-2836
    ISSN (online) 1089-8638
    ISSN 0022-2836
    DOI 10.1016/j.jmb.2016.10.017
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 867: Show issues Location:
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  4. Article: Structural Dynamics in Ras and Related Proteins upon Nucleotide Switching

    Harrison, Rane A / Jia Lu / Martin Carrasco / John Hunter / Anuj Manandhar / Sudershan Gondi / Kenneth D. Westover / John R. Engen

    Journal of Molecular Biology. 2016 Nov. 20, v. 428

    2016  

    Abstract: Structural dynamics of Ras proteins contributes to their activity in signal transduction cascades. Directly targeting Ras proteins with small molecules may rely on the movement of a conserved structural motif, switch II. To understand Ras signaling and ... ...

    Abstract Structural dynamics of Ras proteins contributes to their activity in signal transduction cascades. Directly targeting Ras proteins with small molecules may rely on the movement of a conserved structural motif, switch II. To understand Ras signaling and advance Ras-targeting strategies, experimental methods to measure Ras dynamics are required. Here, we demonstrate the utility of hydrogen–deuterium exchange (HDX) mass spectrometry (MS) to measure Ras dynamics by studying representatives from two branches of the Ras superfamily, Ras and Rho. A comparison of differential deuterium exchange between active (GMPPNP-bound) and inactive (GDP-bound) proteins revealed differences between the families, with the most notable differences occurring in the phosphate-binding loop and switch II. The P-loop exchange signature correlated with switch II dynamics observed in molecular dynamics simulations focused on measuring main-chain movement. HDX provides a means of evaluating Ras protein dynamics, which may be useful for understanding the mechanisms of Ras signaling, including activated signaling of pathologic mutants, and for targeting strategies that rely on protein dynamics.
    Keywords deuterium ; mass spectrometry ; molecular dynamics ; mutants ; proteins ; signal transduction
    Language English
    Dates of publication 2016-1120
    Size p. 4723-4735.
    Publishing place Elsevier Ltd
    Document type Article
    ZDB-ID 80229-3
    ISSN 1089-8638 ; 0022-2836
    ISSN (online) 1089-8638
    ISSN 0022-2836
    DOI 10.1016/j.jmb.2016.10.017
    Database NAL-Catalogue (AGRICOLA)

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  5. Article ; Online: ExoSTING, an extracellular vesicle loaded with STING agonists, promotes tumor immune surveillance.

    Jang, Su Chul / Economides, Kyriakos D / Moniz, Raymond J / Sia, Chang Ling / Lewis, Nuruddeen / McCoy, Christine / Zi, Tong / Zhang, Kelvin / Harrison, Rane A / Lim, Joanne / Dey, Joyoti / Grenley, Marc / Kirwin, Katherine / Ross, Nikki L / Bourdeau, Raymond / Villiger-Oberbek, Agata / Estes, Scott / Xu, Ke / Sanchez-Salazar, Jorge /
    Dooley, Kevin / Dahlberg, William K / Williams, Douglas E / Sathyanarayanan, Sriram

    Communications biology

    2021  Volume 4, Issue 1, Page(s) 497

    Abstract: Cyclic dinucleotide (CDN) agonists of the STimulator of InterferoN Genes (STING) pathway have shown immune activation and tumor clearance in pre-clinical models. However, CDNs administered intratumorally also promote STING activation leading to direct ... ...

    Abstract Cyclic dinucleotide (CDN) agonists of the STimulator of InterferoN Genes (STING) pathway have shown immune activation and tumor clearance in pre-clinical models. However, CDNs administered intratumorally also promote STING activation leading to direct cytotoxicity of many cell types in the tumor microenvironment (TME), systemic inflammation due to rapid tumor extravasation of the CDN, and immune ablation in the TME. These result in a failure to establish immunological memory. ExoSTING, an engineered extracellular vesicle (EV) exogenously loaded with CDN, enhances the potency of CDN and preferentially activates antigen presenting cells in the TME. Following intratumoral injection, exoSTING was retained within the tumor, enhanced local Th1 responses and recruitment of CD8
    MeSH term(s) Animals ; Extracellular Vesicles/physiology ; Female ; Immunologic Surveillance ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Tumor Microenvironment/physiology
    Language English
    Publishing date 2021-04-22
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2399-3642
    ISSN (online) 2399-3642
    DOI 10.1038/s42003-021-02004-5
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  6. Article ; Online: A versatile platform for generating engineered extracellular vesicles with defined therapeutic properties.

    Dooley, Kevin / McConnell, Russell E / Xu, Ke / Lewis, Nuruddeen D / Haupt, Sonya / Youniss, Madeleine R / Martin, Shelly / Sia, Chang Ling / McCoy, Christine / Moniz, Raymond J / Burenkova, Olga / Sanchez-Salazar, Jorge / Jang, Su Chul / Choi, Bryan / Harrison, Rane A / Houde, Damian / Burzyn, Dalia / Leng, Charan / Kirwin, Katherine /
    Ross, Nikki L / Finn, Jonathan D / Gaidukov, Leonid / Economides, Kyriakos D / Estes, Scott / Thornton, James E / Kulman, John D / Sathyanarayanan, Sriram / Williams, Douglas E

    Molecular therapy : the journal of the American Society of Gene Therapy

    2021  Volume 29, Issue 5, Page(s) 1729–1743

    Abstract: Extracellular vesicles (EVs) are an important intercellular communication system facilitating the transfer of macromolecules between cells. Delivery of exogenous cargo tethered to the EV surface or packaged inside the lumen are key strategies for ... ...

    Abstract Extracellular vesicles (EVs) are an important intercellular communication system facilitating the transfer of macromolecules between cells. Delivery of exogenous cargo tethered to the EV surface or packaged inside the lumen are key strategies for generating therapeutic EVs. We identified two "scaffold" proteins, PTGFRN and BASP1, that are preferentially sorted into EVs and enable high-density surface display and luminal loading of a wide range of molecules, including cytokines, antibody fragments, RNA binding proteins, vaccine antigens, Cas9, and members of the TNF superfamily. Molecules were loaded into EVs at high density and exhibited potent in vitro activity when fused to full-length or truncated forms of PTGFRN or BASP1. Furthermore, these engineered EVs retained pharmacodynamic activity in a variety of animal models. This engineering platform provides a simple approach to functionalize EVs with topologically diverse macromolecules and represents a significant advance toward unlocking the therapeutic potential of EVs.
    MeSH term(s) Animals ; Cell Communication ; Drug Delivery Systems ; Extracellular Vesicles/genetics ; Extracellular Vesicles/metabolism ; Extracellular Vesicles/transplantation ; Female ; HEK293 Cells ; Humans ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mice ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Proteins/administration & dosage ; Repressor Proteins/genetics ; Repressor Proteins/metabolism
    Chemical Substances BASP1 protein, human ; Membrane Proteins ; Neoplasm Proteins ; Nerve Tissue Proteins ; PTGFRN protein, human ; Proteins ; Repressor Proteins
    Language English
    Publishing date 2021-01-21
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2010592-7
    ISSN 1525-0024 ; 1525-0016
    ISSN (online) 1525-0024
    ISSN 1525-0016
    DOI 10.1016/j.ymthe.2021.01.020
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5640: Show issues Location:
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  7. Article ; Online: Modulating the strength of hydrogen bond acceptors to achieve low Caco2 efflux for oral bioavailability of PARP inhibitors blocking centrosome clustering.

    Gu, Chungang / Lamb, Michelle L / Johannes, Jeffrey W / Sylvester, Mark A / Eisman, Mark S / Harrison, Rane A / Hu, Haiqing / Kazmirski, Steven / Mikule, Keith / Peng, Bo / Su, Nancy / Wang, Wenxian / Ye, Qing / Zheng, Xiaolan / Lyne, Paul D / Scott, David A

    Bioorganic & medicinal chemistry letters

    2016  Volume 26, Issue 19, Page(s) 4775–4780

    Abstract: During the lead generation and optimization of PARP inhibitors blocking centrosome clustering, it was discovered that increasing hydrogen bond acceptor (HBA) strength improved cellular potency but led to elevated Caco2 and MDR1 efflux and thus poor oral ... ...

    Abstract During the lead generation and optimization of PARP inhibitors blocking centrosome clustering, it was discovered that increasing hydrogen bond acceptor (HBA) strength improved cellular potency but led to elevated Caco2 and MDR1 efflux and thus poor oral bioavailability. Conversely, compounds with lower efflux had reduced potency. The project team was able to improve the bioavailability by reducing efflux through systematic modifications to the strength of the HBA by changing the electronic properties of neighboring groups, whilst maintaining sufficient acceptor strength for potency. Additionally, it was observed that enantiomers with different potency showed similar efflux, which is consistent with the promiscuity of efflux transporters. Eventually, a balance between potency and low efflux was achieved for a set of lead compounds with good bioavailability which allowed the project to progress towards establishing in vivo pharmacokinetic/pharmacodynamic relationships.
    MeSH term(s) Administration, Oral ; Animals ; Biological Availability ; Caco-2 Cells ; Centrosome/metabolism ; Dogs ; Humans ; Hydrogen Bonding ; Madin Darby Canine Kidney Cells ; Mice ; Poly(ADP-ribose) Polymerase Inhibitors/administration & dosage ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacokinetics ; Rats
    Chemical Substances Poly(ADP-ribose) Polymerase Inhibitors
    Language English
    Publishing date 2016--01
    Publishing country England
    Document type Journal Article
    ZDB-ID 1063195-1
    ISSN 1464-3405 ; 0960-894X
    ISSN (online) 1464-3405
    ISSN 0960-894X
    DOI 10.1016/j.bmcl.2016.08.030
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    Zs.A 3203: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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  8. Article ; Online: Therapeutic targeting of oncogenic K-Ras by a covalent catalytic site inhibitor.

    Lim, Sang Min / Westover, Kenneth D / Ficarro, Scott B / Harrison, Rane A / Choi, Hwan Geun / Pacold, Michael E / Carrasco, Martin / Hunter, John / Kim, Nam Doo / Xie, Ting / Sim, Taebo / Jänne, Pasi A / Meyerson, Matthew / Marto, Jarrod A / Engen, John R / Gray, Nathanael S

    Angewandte Chemie (International ed. in English)

    2013  Volume 53, Issue 1, Page(s) 199–204

    Abstract: We report the synthesis of a GDP analogue, SML-8-73-1, and a prodrug derivative, SML-10-70-1, which are selective, direct-acting covalent inhibitors of the K-Ras G12C mutant relative to wild-type Ras. Biochemical and biophysical measurements suggest that ...

    Abstract We report the synthesis of a GDP analogue, SML-8-73-1, and a prodrug derivative, SML-10-70-1, which are selective, direct-acting covalent inhibitors of the K-Ras G12C mutant relative to wild-type Ras. Biochemical and biophysical measurements suggest that modification of K-Ras with SML-8-73-1 renders the protein in an inactive state. These first-in-class covalent K-Ras inhibitors demonstrate that irreversible targeting of the K-Ras guanine-nucleotide binding site is potentially a viable therapeutic strategy for inhibition of Ras signaling.
    MeSH term(s) Catalytic Domain/genetics ; Drug Design ; Signal Transduction ; ras Proteins/chemistry ; ras Proteins/genetics ; ras Proteins/metabolism
    Chemical Substances ras Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2013-11-20
    Publishing country Germany
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2011836-3
    ISSN 1521-3773 ; 1433-7851
    ISSN (online) 1521-3773
    ISSN 1433-7851
    DOI 10.1002/anie.201307387
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