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  1. Article ; Online: Conformational distributions of isolated myosin motor domains encode their mechanochemical properties

    Justin R Porter / Artur Meller / Maxwell I Zimmerman / Michael J Greenberg / Gregory R Bowman

    eLife, Vol

    2020  Volume 9

    Abstract: Myosin motor domains perform an extraordinary diversity of biological functions despite sharing a common mechanochemical cycle. Motors are adapted to their function, in part, by tuning the thermodynamics and kinetics of steps in this cycle. However, it ... ...

    Abstract Myosin motor domains perform an extraordinary diversity of biological functions despite sharing a common mechanochemical cycle. Motors are adapted to their function, in part, by tuning the thermodynamics and kinetics of steps in this cycle. However, it remains unclear how sequence encodes these differences, since biochemically distinct motors often have nearly indistinguishable crystal structures. We hypothesized that sequences produce distinct biochemical phenotypes by modulating the relative probabilities of an ensemble of conformations primed for different functional roles. To test this hypothesis, we modeled the distribution of conformations for 12 myosin motor domains by building Markov state models (MSMs) from an unprecedented two milliseconds of all-atom, explicit-solvent molecular dynamics simulations. Comparing motors reveals shifts in the balance between nucleotide-favorable and nucleotide-unfavorable P-loop conformations that predict experimentally measured duty ratios and ADP release rates better than sequence or individual structures. This result demonstrates the power of an ensemble perspective for interrogating sequence-function relationships.
    Keywords energy landscapes ; machine learning ; markov sate models ; molecular dynamics ; conformational heterogeneity ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 612
    Language English
    Publishing date 2020-05-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Deep learning the structural determinants of protein biochemical properties by comparing structural ensembles with DiffNets

    Michael D. Ward / Maxwell I. Zimmerman / Artur Meller / Moses Chung / S. J. Swamidass / Gregory R. Bowman

    Nature Communications, Vol 12, Iss 1, Pp 1-

    2021  Volume 12

    Abstract: Comparing and contrasting structural ensembles of different protein variants helps connect specific structural features to a protein’s biochemical properties. Here, the authors propose DiffNets, a self-supervised, deep learning method that streamlines ... ...

    Abstract Comparing and contrasting structural ensembles of different protein variants helps connect specific structural features to a protein’s biochemical properties. Here, the authors propose DiffNets, a self-supervised, deep learning method that streamlines this process.
    Keywords Science ; Q
    Language English
    Publishing date 2021-05-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: A cryptic pocket in Ebola VP35 allosterically controls RNA binding

    Matthew A. Cruz / Thomas E. Frederick / Upasana L. Mallimadugula / Sukrit Singh / Neha Vithani / Maxwell I. Zimmerman / Justin R. Porter / Katelyn E. Moeder / Gaya K. Amarasinghe / Gregory R. Bowman

    Nature Communications, Vol 13, Iss 1, Pp 1-

    2022  Volume 10

    Abstract: Many viral proteins are thought to be unlikely candidates for drug discovery as they lack obvious drug binding sites. Here, the authors use computational approaches followed by experimental validation to identify a cryptic pocket within the Ebola virus ... ...

    Abstract Many viral proteins are thought to be unlikely candidates for drug discovery as they lack obvious drug binding sites. Here, the authors use computational approaches followed by experimental validation to identify a cryptic pocket within the Ebola virus protein VP35.
    Keywords Science ; Q
    Language English
    Publishing date 2022-04-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: The SARS-CoV-2 nucleocapsid protein is dynamic, disordered, and phase separates with RNA

    Jasmine Cubuk / Jhullian J. Alston / J. Jeremías Incicco / Sukrit Singh / Melissa D. Stuchell-Brereton / Michael D. Ward / Maxwell I. Zimmerman / Neha Vithani / Daniel Griffith / Jason A. Wagoner / Gregory R. Bowman / Kathleen B. Hall / Andrea Soranno / Alex S. Holehouse

    Nature Communications, Vol 12, Iss 1, Pp 1-

    2021  Volume 17

    Abstract: SARS-CoV-2 nucleocapsid (N) protein is responsible for viral genome packaging. Here the authors employ single-molecule spectroscopy with all-atom simulations to provide the molecular details of N protein and show that it undergoes phase separation with ... ...

    Abstract SARS-CoV-2 nucleocapsid (N) protein is responsible for viral genome packaging. Here the authors employ single-molecule spectroscopy with all-atom simulations to provide the molecular details of N protein and show that it undergoes phase separation with RNA.
    Keywords Science ; Q
    Language English
    Publishing date 2021-03-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Designing small molecules to target cryptic pockets yields both positive and negative allosteric modulators.

    Kathryn M Hart / Katelyn E Moeder / Chris M W Ho / Maxwell I Zimmerman / Thomas E Frederick / Gregory R Bowman

    PLoS ONE, Vol 12, Iss 6, p e

    2017  Volume 0178678

    Abstract: Allosteric drugs, which bind to proteins in regions other than their main ligand-binding or active sites, make it possible to target proteins considered "undruggable" and to develop new therapies that circumvent existing resistance. Despite growing ... ...

    Abstract Allosteric drugs, which bind to proteins in regions other than their main ligand-binding or active sites, make it possible to target proteins considered "undruggable" and to develop new therapies that circumvent existing resistance. Despite growing interest in allosteric drug discovery, rational design is limited by a lack of sufficient structural information about alternative binding sites in proteins. Previously, we used Markov State Models (MSMs) to identify such "cryptic pockets," and here we describe a method for identifying compounds that bind in these cryptic pockets and modulate enzyme activity. Experimental tests validate our approach by revealing both an inhibitor and two activators of TEM β-lactamase (TEM). To identify hits, a library of compounds is first virtually screened against either the crystal structure of a known cryptic pocket or an ensemble of structures containing the same cryptic pocket that is extracted from an MSM. Hit compounds are then screened experimentally and characterized kinetically in individual assays. We identify three hits, one inhibitor and two activators, demonstrating that screening for binding to allosteric sites can result in both positive and negative modulation. The hit compounds have modest effects on TEM activity, but all have higher affinities than previously identified inhibitors, which bind the same cryptic pocket but were found, by chance, via a computational screen targeting the active site. Site-directed mutagenesis of key contact residues predicted by the docking models is used to confirm that the compounds bind in the cryptic pocket as intended. Because hit compounds are identified from docking against both the crystal structure and structures from the MSM, this platform should prove suitable for many proteins, particularly targets whose crystal structures lack obvious druggable pockets, and for identifying both inhibitory and activating small-molecule modulators.
    Keywords Medicine ; R ; Science ; Q
    Subject code 540
    Language English
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: The Cap-Snatching SFTSV Endonuclease Domain Is an Antiviral Target

    Wenjie Wang / Woo-Jin Shin / Bojie Zhang / Younho Choi / Ji-Seung Yoo / Maxwell I. Zimmerman / Thomas E. Frederick / Gregory R. Bowman / Michael L. Gross / Daisy W. Leung / Jae U. Jung / Gaya K. Amarasinghe

    Cell Reports, Vol 30, Iss 1, Pp 153-163.e

    2020  Volume 5

    Abstract: Summary: Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne virus with 12%–30% case mortality rates and is related to the Heartland virus (HRTV) identified in the United States. Together, SFTSV and HRTV are emerging segmented, ... ...

    Abstract Summary: Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne virus with 12%–30% case mortality rates and is related to the Heartland virus (HRTV) identified in the United States. Together, SFTSV and HRTV are emerging segmented, negative-sense RNA viral (sNSV) pathogens with potential global health impact. Here, we characterize the amino-terminal cap-snatching endonuclease domain of SFTSV polymerase (L) and solve a 2.4-Å X-ray crystal structure. While the overall structure is similar to those of other cap-snatching sNSV endonucleases, differences near the C terminus of the SFTSV endonuclease suggest divergence in regulation. Influenza virus endonuclease inhibitors, including the US Food and Drug Administration (FDA) approved Baloxavir (BXA), inhibit the endonuclease activity in in vitro enzymatic assays and in cell-based studies. BXA displays potent activity with a half maximal inhibitory concentration (IC50) of ∼100 nM in enzyme inhibition and an EC50 value of ∼250 nM against SFTSV and HRTV in plaque assays. Together, our data support sNSV endonucleases as an antiviral target. : Wang et al. solve the X-ray crystal structure of SFTSV L endonuclease domain and investigate the characteristics of SFTSV and HRTV endonuclease function. Resulting data support a mechanism for regulation. Baloxavir effectively inhibits the endonuclease activity of SFTSV and HRTV. Keywords: severe fever with thrombocytopenia syndrome virus, Heartland virus, endonuclease, X-ray structure, antiviral target, mass spectrometry, Baloxavir
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2020-01-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article: Antiparallel β-Sheet Structure within the C-Terminal Region of 42-Residue Alzheimer's Amyloid-β Peptides When They Form 150-kDa Oligomers

    Huang, Danting / A.Jeremy Nix / Anant K. Paravastu / Maxwell I. Zimmerman / Patricia K. Martin / Terrone L. Rosenberry

    Journal of Molecular Biology. 2015 July 03, v. 427

    2015  

    Abstract: Understanding the molecular structures of amyloid-β (Aβ) oligomers and underlying assembly pathways will advance our understanding of Alzheimer's disease (AD) at the molecular level. This understanding could contribute to disease prevention, diagnosis, ...

    Abstract Understanding the molecular structures of amyloid-β (Aβ) oligomers and underlying assembly pathways will advance our understanding of Alzheimer's disease (AD) at the molecular level. This understanding could contribute to disease prevention, diagnosis, and treatment strategies, as oligomers play a central role in AD pathology. We have recently presented a procedure for production of 150-kDa oligomeric samples of Aβ(1-42) (the 42-residue variant of the Aβ peptide) that are compatible with solid-state nuclear magnetic resonance (NMR) analysis, and we have shown that these oligomers and amyloid fibrils differ in intermolecular arrangement of β-strands. Here we report new solid-state NMR constraints that indicate antiparallel intermolecular alignment of β-strands within the oligomers. Specifically, 150-kDa Aβ(1-42) oligomers with uniform 13C and 15N isotopic labels at I32, M35, G37, and V40 exhibit β-strand secondary chemical shifts in 2-dimensional (2D) finite-pulse radiofrequency-driven recoupling NMR spectra, spatial proximities between I32 and V40 as well as between M35 and G37 in 2D dipolar-assisted rotational resonance spectra, and close proximity between M35 Hα and G37 Hα in 2D CHHC spectra. Furthermore, 2D dipolar-assisted rotational resonance analysis of an oligomer sample prepared with 30% labeled peptide indicates that the I32-V40 and M35-G37 contacts are between residues on different molecules. We employ molecular modeling to compare the newly derived experimental constraints with previously proposed geometries for arrangement of Aβ molecules into oligomers.
    Keywords Alzheimer disease ; amyloid ; carbon ; disease diagnosis ; disease prevention ; isotope labeling ; molecular models ; nitrogen ; nuclear magnetic resonance spectroscopy ; peptides ; protein quaternary structure ; protein subunits ; stable isotopes ; therapeutics
    Language English
    Dates of publication 2015-0703
    Size p. 2319-2328.
    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.2015.04.004
    Database NAL-Catalogue (AGRICOLA)

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  8. Article ; Online: Prediction of New Stabilizing Mutations Based on Mechanistic Insights from Markov State Models

    Maxwell I. Zimmerman / Kathryn M. Hart / Carrie A. Sibbald / Thomas E. Frederick / John R. Jimah / Catherine R. Knoverek / Niraj H. Tolia / Gregory R. Bowman

    ACS Central Science, Vol 3, Iss 12, Pp 1311-

    2017  Volume 1321

    Keywords Chemistry ; QD1-999
    Language English
    Publishing date 2017-11-01T00:00:00Z
    Publisher American Chemical Society
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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