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  1. Article ; Online: High-resolution structure of intramolecularly proteolyzed human mucin-1 SEA domain.

    Noguera, Martín E / Jakoncic, Jean / Ermácora, Mario R

    Biochimica et biophysica acta. Proteins and proteomics

    2020  Volume 1868, Issue 3, Page(s) 140361

    Abstract: SEA domains are ubiquitous in large proteins associated with highly glycosylated environments. Certain SEA domains undergo intramolecular proteolysis involving a nucleophilic attack of a serine hydroxyl group on the preceding glycine carbonyl. The mucin- ... ...

    Abstract SEA domains are ubiquitous in large proteins associated with highly glycosylated environments. Certain SEA domains undergo intramolecular proteolysis involving a nucleophilic attack of a serine hydroxyl group on the preceding glycine carbonyl. The mucin-1 (MUC1) SEA domain has been extensively investigated as a model of intramolecular proteolysis. Since neither a general base, a general acid, nor an oxyanion hole could be identified in MUC1 SEA, it has been suggested that proteolysis is accelerated by a non-planarity of the scissile peptide bond imposed by protein folding. A reactant distorted peptide bond has been also invoked to explain the autoproteolysis of several unrelated proteins. However, the only evidence of peptide distortion in MUC1 SEA stems from molecular dynamic simulations of the reactant modeled upon a single NMR structure of the cleaved product. We report the first high-resolution X-ray structure of cleaved MUC1 SEA. Structural comparison with uncleaved SEA domains suggests that the number of residues evolutionarily inserted in the cleaved loop of MUC1 SEA precludes the formation of a properly hydrogen-bonded beta turn. By sequence analysis, we show that this conformational frustration is shared by all known cleaved SEA domains. In addition, alternative conformations of the uncleaved precursor could be modeled in which the scissile peptide bond is planar. The implications of these structures for autoproteolysis are discussed in the light of the previous research on autoproteolysis.
    MeSH term(s) Crystallography, X-Ray ; Models, Molecular ; Mucin-1/chemistry ; Mucin-1/metabolism ; Protein Domains ; Proteolysis
    Chemical Substances MUC1 protein, human ; Mucin-1
    Language English
    Publishing date 2020-01-07
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2918798-9
    ISSN 1878-1454 ; 1570-9639
    ISSN (online) 1878-1454
    ISSN 1570-9639
    DOI 10.1016/j.bbapap.2020.140361
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  2. Article: High-resolution structure of intramolecularly proteolyzed human mucin-1 SEA domain

    Noguera, Martín E / Jakoncic, Jean / Ermácora, Mario R

    Biochimica et biophysica acta. 2020 Mar., v. 1868, no. 3

    2020  

    Abstract: SEA domains are ubiquitous in large proteins associated with highly glycosylated environments. Certain SEA domains undergo intramolecular proteolysis involving a nucleophilic attack of a serine hydroxyl group on the preceding glycine carbonyl. The mucin- ... ...

    Abstract SEA domains are ubiquitous in large proteins associated with highly glycosylated environments. Certain SEA domains undergo intramolecular proteolysis involving a nucleophilic attack of a serine hydroxyl group on the preceding glycine carbonyl. The mucin-1 (MUC1) SEA domain has been extensively investigated as a model of intramolecular proteolysis. Since neither a general base, a general acid, nor an oxyanion hole could be identified in MUC1 SEA, it has been suggested that proteolysis is accelerated by a non-planarity of the scissile peptide bond imposed by protein folding. A reactant distorted peptide bond has been also invoked to explain the autoproteolysis of several unrelated proteins. However, the only evidence of peptide distortion in MUC1 SEA stems from molecular dynamic simulations of the reactant modeled upon a single NMR structure of the cleaved product. We report the first high-resolution X-ray structure of cleaved MUC1 SEA. Structural comparison with uncleaved SEA domains suggests that the number of residues evolutionarily inserted in the cleaved loop of MUC1 SEA precludes the formation of a properly hydrogen-bonded beta turn. By sequence analysis, we show that this conformational frustration is shared by all known cleaved SEA domains. In addition, alternative conformations of the uncleaved precursor could be modeled in which the scissile peptide bond is planar. The implications of these structures for autoproteolysis are discussed in the light of the previous research on autoproteolysis.
    Keywords Lewis bases ; X-radiation ; glycine (amino acid) ; glycosylation ; humans ; hydrogen bonding ; models ; moieties ; nuclear magnetic resonance spectroscopy ; oxyanions ; peptides ; protein folding ; proteins ; proteolysis ; sequence analysis ; serine
    Language English
    Dates of publication 2020-03
    Publishing place Elsevier B.V.
    Document type Article
    ZDB-ID 2918798-9
    ISSN 1878-1454 ; 1570-9639
    ISSN (online) 1878-1454
    ISSN 1570-9639
    DOI 10.1016/j.bbapap.2020.140361
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  3. Article ; Online: A simple technique to classify diffraction data from dynamic proteins according to individual polymorphs.

    Nguyen, Thu / Phan, Kim L / Kozakov, Dima / Gabelli, Sandra B / Kreitler, Dale F / Andrews, Lawrence C / Jakoncic, Jean / Sweet, Robert M / Soares, Alexei S / Bernstein, Herbert J

    Acta crystallographica. Section D, Structural biology

    2022  Volume 78, Issue Pt 3, Page(s) 268–277

    Abstract: One often observes small but measurable differences in the diffraction data measured from different crystals of a single protein. These differences might reflect structural differences in the protein and may reveal the natural dynamism of the molecule in ...

    Abstract One often observes small but measurable differences in the diffraction data measured from different crystals of a single protein. These differences might reflect structural differences in the protein and may reveal the natural dynamism of the molecule in solution. Partitioning these mixed-state data into single-state clusters is a critical step that could extract information about the dynamic behavior of proteins from hundreds or thousands of single-crystal data sets. Mixed-state data can be obtained deliberately (through intentional perturbation) or inadvertently (while attempting to measure highly redundant single-crystal data). To the extent that different states adopt different molecular structures, one expects to observe differences in the crystals; each of the polystates will create a polymorph of the crystals. After mixed-state diffraction data have been measured, deliberately or inadvertently, the challenge is to sort the data into clusters that may represent relevant biological polystates. Here, this problem is addressed using a simple multi-factor clustering approach that classifies each data set using independent observables, thereby assigning each data set to the correct location in conformational space. This procedure is illustrated using two independent observables, unit-cell parameters and intensities, to cluster mixed-state data from chymotrypsinogen (ChTg) crystals. It is observed that the data populate an arc of the reaction trajectory as ChTg is converted into chymotrypsin.
    MeSH term(s) Models, Molecular ; Molecular Conformation ; Molecular Structure ; Proteins
    Chemical Substances Proteins
    Language English
    Publishing date 2022-02-18
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2968623-4
    ISSN 2059-7983 ; 0907-4449
    ISSN (online) 2059-7983
    ISSN 0907-4449
    DOI 10.1107/S2059798321013425
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  4. Article ; Online: EstG is a novel esterase required for cell envelope integrity in Caulobacter.

    Daitch, Allison K / Orsburn, Benjamin C / Chen, Zan / Alvarez, Laura / Eberhard, Colten D / Sundararajan, Kousik / Zeinert, Rilee / Kreitler, Dale F / Jakoncic, Jean / Chien, Peter / Cava, Felipe / Gabelli, Sandra B / Goley, Erin D

    Current biology : CB

    2022  Volume 33, Issue 2, Page(s) 228–240.e7

    Abstract: Proper regulation of the bacterial cell envelope is critical for cell survival. Identification and characterization of enzymes that maintain cell envelope homeostasis is crucial, as they can be targets for effective antibiotics. In this study, we have ... ...

    Abstract Proper regulation of the bacterial cell envelope is critical for cell survival. Identification and characterization of enzymes that maintain cell envelope homeostasis is crucial, as they can be targets for effective antibiotics. In this study, we have identified a novel enzyme, called EstG, whose activity protects cells from a variety of lethal assaults in the ⍺-proteobacterium Caulobacter crescentus. Despite homology to transpeptidase family cell wall enzymes and an ability to protect against cell-wall-targeting antibiotics, EstG does not demonstrate biochemical activity toward cell wall substrates. Instead, EstG is genetically connected to the periplasmic enzymes OpgH and BglX, responsible for synthesis and hydrolysis of osmoregulated periplasmic glucans (OPGs), respectively. The crystal structure of EstG revealed similarities to esterases and transesterases, and we demonstrated esterase activity of EstG in vitro. Using biochemical fractionation, we identified a cyclic hexamer of glucose as a likely substrate of EstG. This molecule is the first OPG described in Caulobacter and establishes a novel class of OPGs, the regulation and modification of which are important for stress survival and adaptation to fluctuating environments. Our data indicate that EstG, BglX, and OpgH comprise a previously unknown OPG pathway in Caulobacter. Ultimately, we propose that EstG is a novel enzyme that instead of acting on the cell wall, acts on cyclic OPGs to provide resistance to a variety of cellular stresses.
    MeSH term(s) Caulobacter/metabolism ; Esterases ; Cell Membrane/metabolism ; Cell Wall/metabolism ; Caulobacter crescentus/metabolism ; Anti-Bacterial Agents ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism
    Chemical Substances Esterases (EC 3.1.-) ; Anti-Bacterial Agents ; Bacterial Proteins
    Language English
    Publishing date 2022-12-13
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1071731-6
    ISSN 1879-0445 ; 0960-9822
    ISSN (online) 1879-0445
    ISSN 0960-9822
    DOI 10.1016/j.cub.2022.11.037
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  5. Article ; Online: Serial crystallography with multi-stage merging of thousands of images.

    Soares, Alexei S / Yamada, Yusuke / Jakoncic, Jean / McSweeney, Sean / Sweet, Robert M / Skinner, John / Foadi, James / Fuchs, Martin R / Schneider, Dieter K / Shi, Wuxian / Andi, Babak / Andrews, Lawrence C / Bernstein, Herbert J

    Acta crystallographica. Section F, Structural biology communications

    2022  Volume 78, Issue Pt 7, Page(s) 281–288

    Abstract: KAMO and BLEND provide particularly effective tools to automatically manage the merging of large numbers of data sets from serial crystallography. The requirement for manual intervention in the process can be reduced by extending BLEND to support ... ...

    Abstract KAMO and BLEND provide particularly effective tools to automatically manage the merging of large numbers of data sets from serial crystallography. The requirement for manual intervention in the process can be reduced by extending BLEND to support additional clustering options such as the use of more accurate cell distance metrics and the use of reflection-intensity correlation coefficients to infer `distances' among sets of reflections. This increases the sensitivity to differences in unit-cell parameters and allows clustering to assemble nearly complete data sets on the basis of intensity or amplitude differences. If the data sets are already sufficiently complete to permit it, one applies KAMO once and clusters the data using intensities only. When starting from incomplete data sets, one applies KAMO twice, first using unit-cell parameters. In this step, either the simple cell vector distance of the original BLEND or the more sensitive NCDist is used. This step tends to find clusters of sufficient size such that, when merged, each cluster is sufficiently complete to allow reflection intensities or amplitudes to be compared. One then uses KAMO again using the correlation between reflections with a common hkl to merge clusters in a way that is sensitive to structural differences that may not have perturbed the unit-cell parameters sufficiently to make meaningful clusters. Many groups have developed effective clustering algorithms that use a measurable physical parameter from each diffraction still or wedge to cluster the data into categories which then can be merged, one hopes, to yield the electron density from a single protein form. Since these physical parameters are often largely independent of one another, it should be possible to greatly improve the efficacy of data-clustering software by using a multi-stage partitioning strategy. Here, one possible approach to multi-stage data clustering is demonstrated. The strategy is to use unit-cell clustering until the merged data are sufficiently complete and then to use intensity-based clustering. Using this strategy, it is demonstrated that it is possible to accurately cluster data sets from crystals that have subtle differences.
    MeSH term(s) Algorithms ; Cluster Analysis ; Crystallography, X-Ray ; Proteins/chemistry ; Software
    Chemical Substances Proteins
    Language English
    Publishing date 2022-07-04
    Publishing country United States
    Document type Journal Article
    ISSN 2053-230X
    ISSN (online) 2053-230X
    DOI 10.1107/S2053230X22006422
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  6. Article: Structural Insights into the Induced-fit Inhibition of Fascin by a Small-Molecule Inhibitor

    Huang, Jianyun / Dey, Raja / Wang, Yufeng / Jakoncic, Jean / Kurinov, Igor / Huang, Xin-Yun

    Journal of molecular biology. 2018 Apr. 27, v. 430

    2018  

    Abstract: Tumor metastasis is responsible for ~90% of all cancer deaths. One of the key steps of tumor metastasis is tumor cell migration and invasion. Filopodia are cell surface extensions that are critical for tumor cell migration. Fascin protein is the main ... ...

    Abstract Tumor metastasis is responsible for ~90% of all cancer deaths. One of the key steps of tumor metastasis is tumor cell migration and invasion. Filopodia are cell surface extensions that are critical for tumor cell migration. Fascin protein is the main actin-bundling protein in filopodia. Small-molecule fascin inhibitors block tumor cell migration, invasion, and metastasis. Here we present the structural basis for the mechanism of action of these small-molecule fascin inhibitors. X-ray crystal structural analysis of a complex of fascin and a fascin inhibitor shows that binding of the fascin inhibitor to the hydrophobic cleft between the domains 1 and 2 of fascin induces a ~35ᵒ rotation of domain 1, leading to the distortion of both the actin-binding sites 1 and 2 on fascin. Furthermore, the crystal structures of an inhibitor alone indicate that the conformations of the small-molecule inhibitors are dynamic. Mutations of the inhibitor-interacting residues decrease the sensitivity of fascin to the inhibitors. Our studies provide structural insights into the molecular mechanism of fascin protein function as well as the action of small-molecule fascin inhibitors.
    Keywords X-radiation ; cell movement ; crystal structure ; hydrophobicity ; mechanism of action ; metastasis ; mutation ; neoplasm cells ; neoplasms ; pseudopodia
    Language English
    Dates of publication 2018-0427
    Size p. 1324-1335.
    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.2018.03.009
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  7. Article ; Online: Structural Insights into the Induced-fit Inhibition of Fascin by a Small-Molecule Inhibitor.

    Huang, Jianyun / Dey, Raja / Wang, Yufeng / Jakoncic, Jean / Kurinov, Igor / Huang, Xin-Yun

    Journal of molecular biology

    2018  Volume 430, Issue 9, Page(s) 1324–1335

    Abstract: Tumor metastasis is responsible for ~90% of all cancer deaths. One of the key steps of tumor metastasis is tumor cell migration and invasion. Filopodia are cell surface extensions that are critical for tumor cell migration. Fascin protein is the main ... ...

    Abstract Tumor metastasis is responsible for ~90% of all cancer deaths. One of the key steps of tumor metastasis is tumor cell migration and invasion. Filopodia are cell surface extensions that are critical for tumor cell migration. Fascin protein is the main actin-bundling protein in filopodia. Small-molecule fascin inhibitors block tumor cell migration, invasion, and metastasis. Here we present the structural basis for the mechanism of action of these small-molecule fascin inhibitors. X-ray crystal structural analysis of a complex of fascin and a fascin inhibitor shows that binding of the fascin inhibitor to the hydrophobic cleft between the domains 1 and 2 of fascin induces a ~35
    MeSH term(s) Binding Sites ; Carrier Proteins/chemistry ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Crystallography, X-Ray ; Humans ; Microfilament Proteins/chemistry ; Microfilament Proteins/genetics ; Microfilament Proteins/metabolism ; Models, Molecular ; Mutation ; Protein Binding ; Protein Conformation ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology
    Chemical Substances Carrier Proteins ; FSCN1 protein, human ; Microfilament Proteins ; Small Molecule Libraries
    Language English
    Publishing date 2018-03-21
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 80229-3
    ISSN 1089-8638 ; 0022-2836
    ISSN (online) 1089-8638
    ISSN 0022-2836
    DOI 10.1016/j.jmb.2018.03.009
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    Zs.A 867: Show issues Location:
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  8. Article ; Online: Hepatitis C virus NS3/4A inhibitors and other drug-like compounds as covalent binders of SARS-CoV-2 main protease.

    Andi, Babak / Kumaran, Desigan / Kreitler, Dale F / Soares, Alexei S / Keereetaweep, Jantana / Jakoncic, Jean / Lazo, Edwin O / Shi, Wuxian / Fuchs, Martin R / Sweet, Robert M / Shanklin, John / Adams, Paul D / Schmidt, Jurgen G / Head, Martha S / McSweeney, Sean

    Scientific reports

    2022  Volume 12, Issue 1, Page(s) 12197

    Abstract: Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), threatens global public health. The world needs rapid development of new antivirals and vaccines to control the current pandemic and to ... ...

    Abstract Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), threatens global public health. The world needs rapid development of new antivirals and vaccines to control the current pandemic and to control the spread of the variants. Among the proteins synthesized by the SARS-CoV-2 genome, main protease (M
    MeSH term(s) Antiviral Agents/therapeutic use ; COVID-19/drug therapy ; Coronavirus 3C Proteases ; Cysteine Endopeptidases/metabolism ; Hepacivirus/metabolism ; Humans ; Molecular Docking Simulation ; Protease Inhibitors/chemistry ; SARS-CoV-2 ; Viral Nonstructural Proteins/genetics
    Chemical Substances Antiviral Agents ; Protease Inhibitors ; Viral Nonstructural Proteins ; 3C-like proteinase, SARS-CoV-2 (EC 3.4.22.-) ; Cysteine Endopeptidases (EC 3.4.22.-) ; Coronavirus 3C Proteases (EC 3.4.22.28)
    Language English
    Publishing date 2022-07-16
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-022-15930-z
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  9. Article ; Online: Robotic sample changers for macromolecular X-ray crystallography and biological small-angle X-ray scattering at the National Synchrotron Light Source II. Corrigendum.

    Lazo, Edwin O / Antonelli, Stephen / Aishima, Jun / Bernstein, Herbert J / Bhogadi, Dileep / Fuchs, Martin R / Guichard, Nicolas / McSweeney, Sean / Myers, Stuart / Qian, Kun / Schneider, Dieter / Shea-McCarthy, Grace / Skinner, John / Sweet, Robert / Yang, Lin / Jakoncic, Jean

    Journal of synchrotron radiation

    2022  Volume 29, Issue Pt 1, Page(s) 280

    Abstract: A correction in the paper by Lazo et al. [(2021). J. Synchrotron Rad. 28, 1649-1661] is made. ...

    Abstract A correction in the paper by Lazo et al. [(2021). J. Synchrotron Rad. 28, 1649-1661] is made.
    Language English
    Publishing date 2022-01-01
    Publishing country United States
    Document type Published Erratum
    ZDB-ID 2021413-3
    ISSN 1600-5775 ; 0909-0495
    ISSN (online) 1600-5775
    ISSN 0909-0495
    DOI 10.1107/S1600577521013205
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  10. Article ; Online: Structure-guided studies of the SHP-1/JAK1 interaction provide new insights into phosphatase catalytic domain substrate recognition.

    Alicea-Velázquez, Nilda L / Jakoncic, Jean / Boggon, Titus J

    Journal of structural biology

    2013  Volume 181, Issue 3, Page(s) 243–251

    Abstract: SHP-1 (PTPN6) is a member of the SHP sub-family of protein tyrosine phosphatases and plays a critical role in the regulation of the JAK/STAT signaling pathway. Previous studies suggested that SHP-1 contains a PTP1B-like second phosphotyrosine pocket that ...

    Abstract SHP-1 (PTPN6) is a member of the SHP sub-family of protein tyrosine phosphatases and plays a critical role in the regulation of the JAK/STAT signaling pathway. Previous studies suggested that SHP-1 contains a PTP1B-like second phosphotyrosine pocket that allows for binding of tandem phosphotyrosine residues, such as those found in the activation loop of JAK kinases. To discover the structural nature of the interaction between SHP-1 and the JAK family member, JAK1, we determined the 1.8Å co-crystal structure of the SHP-1 catalytic domain and a JAK1-derived substrate peptide. This structure reveals electron density for only one bound phosphotyrosine residue. To investigate the role of the predicted second site pocket we determined the structures of SHP-1 in complex with phosphate and sulfate to 1.37Å and 1.7Å, respectively, and performed anomalous scattering experiments for a selenate-soaked crystal. These crystallographic data suggest that SHP-1 does not contain a PTP1B-like second site pocket. This conclusion is further supported by analysis of the relative dephosphorylation and binding affinities of mono- and tandem-phosphorylated peptide substrates. The crystal structures instead indicate that SHP-1 contains an extended C-terminal helix α2' incompatible with the predicted second phosphotyrosine binding site. This study suggests that SHP-1 defines a new category of PTP1B-like protein tyrosine phosphatases with a hindered second phosphotyrosine pocket.
    MeSH term(s) Calorimetry ; Catalytic Domain ; Janus Kinase 1/chemistry ; Janus Kinase 1/metabolism ; Protein Binding ; Protein Structure, Secondary ; Protein Tyrosine Phosphatase, Non-Receptor Type 6/chemistry ; Protein Tyrosine Phosphatase, Non-Receptor Type 6/metabolism ; X-Ray Diffraction
    Chemical Substances Janus Kinase 1 (EC 2.7.10.2) ; Protein Tyrosine Phosphatase, Non-Receptor Type 6 (EC 3.1.3.48)
    Language English
    Publishing date 2013-01-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1032718-6
    ISSN 1095-8657 ; 1047-8477
    ISSN (online) 1095-8657
    ISSN 1047-8477
    DOI 10.1016/j.jsb.2012.12.009
    Database MEDical Literature Analysis and Retrieval System OnLINE

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