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  1. Article: Mirolysin structures open a window on gum disease.

    Radisky, Evette S

    IUCrJ

    2020  Volume 7, Issue Pt 1, Page(s) 3–4

    Abstract: Guevara, Rodriguez- ... ...

    Abstract Guevara, Rodriguez-Banqueri
    Language English
    Publishing date 2020-01-01
    Publishing country England
    Document type Journal Article
    ZDB-ID 2754953-7
    ISSN 2052-2525
    ISSN 2052-2525
    DOI 10.1107/S2052252519016968
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Engineering Selective TIMPs Using a Counter-Selective Screening Strategy.

    Ahmadighadykolaei, Hannaneh / Radisky, Evette S / Raeeszadeh-Sarmazdeh, Maryam

    Methods in molecular biology (Clifton, N.J.)

    2023  Volume 2747, Page(s) 257–278

    Abstract: The yeast surface display platform provides a powerful approach for screening protein diversity libraries to identify binders with an enhanced affinity toward a binding partner. Here, we describe an adaptation of the approach to identify binders with ... ...

    Abstract The yeast surface display platform provides a powerful approach for screening protein diversity libraries to identify binders with an enhanced affinity toward a binding partner. Here, we describe an adaptation of the approach to identify binders with enhanced specificity toward one among multiple closely related binding partners. Specifically, we describe methods for engineering selective matrix metalloproteinase (MMP) inhibitors via yeast surface display of a tissue inhibitor of metalloproteinase (TIMP) diversity library coupled with a counter-selective screening strategy. This protocol may also be employed for developing selective protein binders or inhibitors toward other targets.
    MeSH term(s) Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Matrix Metalloproteinase Inhibitors/metabolism ; Proteins ; Metalloproteases ; Tissue Inhibitor of Metalloproteinase-1/metabolism
    Chemical Substances Matrix Metalloproteinase Inhibitors ; Proteins ; Metalloproteases (EC 3.4.-) ; Tissue Inhibitor of Metalloproteinase-1
    Language English
    Publishing date 2023-10-12
    Publishing country United States
    Document type Journal Article
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-0716-3589-6_20
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Structure and computation-guided yeast surface display for the evolution of TIMP-based matrix metalloproteinase inhibitors.

    Shoari, Alireza / Khalili-Tanha, Ghazaleh / Coban, Mathew A / Radisky, Evette S

    Frontiers in molecular biosciences

    2023  Volume 10, Page(s) 1321956

    Abstract: The study of protein-protein interactions (PPIs) and the engineering of protein-based inhibitors often employ two distinct strategies. One approach leverages the power of combinatorial libraries, displaying large ensembles of mutant proteins, for example, ...

    Abstract The study of protein-protein interactions (PPIs) and the engineering of protein-based inhibitors often employ two distinct strategies. One approach leverages the power of combinatorial libraries, displaying large ensembles of mutant proteins, for example, on the yeast cell surface, to select binders. Another approach harnesses computational modeling, sifting through an astronomically large number of protein sequences and attempting to predict the impact of mutations on PPI binding energy. Individually, each approach has inherent limitations, but when combined, they generate superior outcomes across diverse protein engineering endeavors. This synergistic integration of approaches aids in identifying novel binders and inhibitors, fine-tuning specificity and affinity for known binding partners, and detailed mapping of binding epitopes. It can also provide insight into the specificity profiles of varied PPIs. Here, we outline strategies for directing the evolution of tissue inhibitors of metalloproteinases (TIMPs), which act as natural inhibitors of matrix metalloproteinases (MMPs). We highlight examples wherein design of combinatorial TIMP libraries using structural and computational insights and screening these libraries of variants using yeast surface display (YSD), has successfully optimized for MMP binding and selectivity, and conferred insight into the PPIs involved.
    Language English
    Publishing date 2023-11-23
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2814330-9
    ISSN 2296-889X
    ISSN 2296-889X
    DOI 10.3389/fmolb.2023.1321956
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  4. Article ; Online: Designed Loop Extension Followed by Combinatorial Screening Confers High Specificity to a Broad Matrix Metalloproteinase Inhibitor

    Bonadio, Alessandro / Wenig, Bernhard L. / Hockla, Alexandra / Radisky, Evette S. / Shifman, Julia M.

    Journal of Molecular Biology. 2023 Apr. 15, p.168095-

    2023  , Page(s) 168095–

    Abstract: Matrix metalloproteinases (MMPs) are key drivers of various diseases, including cancer. Development of selective probes and drugs capable of selectively inhibiting the individual members of the large MMP family remains a persistent challenge. The ... ...

    Abstract Matrix metalloproteinases (MMPs) are key drivers of various diseases, including cancer. Development of selective probes and drugs capable of selectively inhibiting the individual members of the large MMP family remains a persistent challenge. The inhibitory N-terminal domain of tissue inhibitor of metalloproteinases-2 (N-TIMP2), a natural broad MMP inhibitor, can provide a scaffold for protein engineering to create more selective MMP inhibitors. Here, we pursued a unique approach harnessing both computational design and combinatorial screening to confer high binding specificity toward a target MMP in preference to an anti-target MMP. We designed a loop extension of N-TIMP2 to allow new interactions with the non-conserved MMP surface and generated an efficient focused library for yeast surface display, which was then screened for high binding to the target MMP-14 and low binding to anti-target MMP-3. Deep sequencing analysis identified the most promising variants, which were expressed, purified, and tested for selectivity of inhibition. Our best N-TIMP2 variant exhibited 29 pM binding affinity to MMP-14 and 2.4 µM affinity to MMP-3, revealing 7500-fold greater specificity than WT N-TIMP2. High-confidence structural models were obtained by including NGS data in the AlphaFold multiple sequence alignment. The modeling together with experimental mutagenesis validated our design predictions, demonstrating that the loop extension packs tightly against non-conserved residues on MMP-14 and clashes with MMP-3. This study demonstrates how introduction of loop extensions in a manner guided by target protein conservation data and loop design can offer an attractive strategy to achieve specificity in design of protein ligands.
    Keywords ligands ; metalloproteinases ; molecular biology ; mutagenesis ; sequence alignment ; yeasts ; protein loop engineering ; protein engineering ; protein design ; protein–protein interaction ; binding specificity ; protein structure ; molecular modelling ; matrix metalloproteinase, MMP ; tissue inhibitor of metalloproteinases, TIMP
    Language English
    Dates of publication 2023-0415
    Publishing place Elsevier Ltd
    Document type Article ; Online
    Note Pre-press version
    ZDB-ID 80229-3
    ISSN 1089-8638 ; 0022-2836
    ISSN (online) 1089-8638
    ISSN 0022-2836
    DOI 10.1016/j.jmb.2023.168095
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    Z 4' 63/108: Show issues

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  5. Article: Bad Tumors Made Worse: SPINK1.

    Mehner, Christine / Radisky, Evette S

    Frontiers in cell and developmental biology

    2019  Volume 7, Page(s) 10

    Language English
    Publishing date 2019-02-04
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2737824-X
    ISSN 2296-634X
    ISSN 2296-634X
    DOI 10.3389/fcell.2019.00010
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  6. Article ; Online: Designed Loop Extension Followed by Combinatorial Screening Confers High Specificity to a Broad Matrix MetalloproteinaseInhibitor.

    Bonadio, Alessandro / Wenig, Bernhard L / Hockla, Alexandra / Radisky, Evette S / Shifman, Julia M

    Journal of molecular biology

    2023  Volume 435, Issue 13, Page(s) 168095

    Abstract: Matrix metalloproteinases (MMPs) are key drivers of various diseases, including cancer. Development of probes and drugs capable of selectively inhibiting the individual members of the large MMP family remains a persistent challenge. The inhibitory N- ... ...

    Abstract Matrix metalloproteinases (MMPs) are key drivers of various diseases, including cancer. Development of probes and drugs capable of selectively inhibiting the individual members of the large MMP family remains a persistent challenge. The inhibitory N-terminal domain of tissue inhibitor of metalloproteinases-2 (N-TIMP2), a natural broad MMP inhibitor, can provide a scaffold for protein engineering to create more selective MMP inhibitors. Here, we pursued a unique approach harnessing both computational design and combinatorial screening to confer high binding specificity toward a target MMP in preference to an anti-target MMP. We designed a loop extension of N-TIMP2 to allow new interactions with the non-conserved MMP surface and generated an efficient focused library for yeast surface display, which was then screened for high binding to the target MMP-14 and low binding to anti-target MMP-3. Deep sequencing analysis identified the most promising variants, which were expressed, purified, and tested for selectivity of inhibition. Our best N-TIMP2 variant exhibited 29 pM binding affinity to MMP-14 and 2.4 µM affinity to MMP-3, revealing 7500-fold greater specificity than WT N-TIMP2. High-confidence structural models were obtained by including NGS data in the AlphaFold multiple sequence alignment. The modeling together with experimental mutagenesis validated our design predictions, demonstrating that the loop extension packs tightly against non-conserved residues on MMP-14 and clashes with MMP-3. This study demonstrates how introduction of loop extensions in a manner guided by target protein conservation data and loop design can offer an attractive strategy to achieve specificity in design of protein ligands.
    MeSH term(s) Matrix Metalloproteinase 14/genetics ; Matrix Metalloproteinase 14/chemistry ; Matrix Metalloproteinase 14/metabolism ; Matrix Metalloproteinase 3 ; Matrix Metalloproteinase Inhibitors/chemistry ; Matrix Metalloproteinase Inhibitors/pharmacology ; Mutagenesis ; Protein Engineering
    Chemical Substances Matrix Metalloproteinase 14 (EC 3.4.24.80) ; Matrix Metalloproteinase 3 (EC 3.4.24.17) ; Matrix Metalloproteinase Inhibitors
    Language English
    Publishing date 2023-04-15
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80229-3
    ISSN 1089-8638 ; 0022-2836
    ISSN (online) 1089-8638
    ISSN 0022-2836
    DOI 10.1016/j.jmb.2023.168095
    Database MEDical Literature Analysis and Retrieval System OnLINE

    Full text online

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 867: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
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  7. Article ; Online: PRSS3/mesotrypsin in prostate cancer progression: implications for translational medicine.

    Radisky, Evette S

    Asian journal of andrology

    2013  Volume 15, Issue 4, Page(s) 439–440

    MeSH term(s) Animals ; Humans ; Male ; Prostatic Neoplasms/drug therapy ; Prostatic Neoplasms/metabolism ; Trypsin/genetics ; Trypsin/metabolism ; Trypsin Inhibitors/pharmacology
    Chemical Substances Trypsin Inhibitors ; Trypsin (EC 3.4.21.4)
    Language English
    Publishing date 2013-03-18
    Publishing country China
    Document type Journal Article ; Comment
    ZDB-ID 2075824-8
    ISSN 1745-7262 ; 1008-682X
    ISSN (online) 1745-7262
    ISSN 1008-682X
    DOI 10.1038/aja.2013.14
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5739: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
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  8. Article: Utilizing genetic code expansion to modify N-TIMP2 specificity towards MMP-2, MMP-9, and MMP-14.

    Hayun, Hezi / Coban, Matt / Bhagat, Ashok Kumar / Ozer, Eden / Alfonta, Lital / Caulfield, Thomas R / Radisky, Evette S / Papo, Niv

    Research square

    2023  

    Abstract: Matrix metalloproteinases (MMPs) regulate the degradation of extracellular matrix (ECM) components in biological processes. MMP activity is controlled by natural tissue inhibitors of metalloproteinases (TIMPs) that non-selectively inhibit the function of ...

    Abstract Matrix metalloproteinases (MMPs) regulate the degradation of extracellular matrix (ECM) components in biological processes. MMP activity is controlled by natural tissue inhibitors of metalloproteinases (TIMPs) that non-selectively inhibit the function of multiple MMPs via interaction with the MMPs' Zn
    Language English
    Publishing date 2023-01-16
    Publishing country United States
    Document type Preprint
    DOI 10.21203/rs.3.rs-2446107/v1
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  9. Article ; Online: Utilizing genetic code expansion to modify N-TIMP2 specificity towards MMP-2, MMP-9, and MMP-14.

    Hayun, Hezi / Coban, Matt / Bhagat, Ashok Kumar / Ozer, Eden / Alfonta, Lital / Caulfield, Thomas R / Radisky, Evette S / Papo, Niv

    Scientific reports

    2023  Volume 13, Issue 1, Page(s) 5186

    Abstract: Matrix metalloproteinases (MMPs) regulate the degradation of extracellular matrix (ECM) components in biological processes. MMP activity is controlled by natural tissue inhibitors of metalloproteinases (TIMPs) that non-selectively inhibit the function of ...

    Abstract Matrix metalloproteinases (MMPs) regulate the degradation of extracellular matrix (ECM) components in biological processes. MMP activity is controlled by natural tissue inhibitors of metalloproteinases (TIMPs) that non-selectively inhibit the function of multiple MMPs via interaction with the MMPs' Zn
    MeSH term(s) Tissue Inhibitor of Metalloproteinase-2/genetics ; Tissue Inhibitor of Metalloproteinase-2/metabolism ; Matrix Metalloproteinase 2/genetics ; Matrix Metalloproteinase 2/metabolism ; Matrix Metalloproteinase 9/genetics ; Matrix Metalloproteinase 14 ; Levodopa ; Tissue Inhibitor of Metalloproteinases/genetics
    Chemical Substances Tissue Inhibitor of Metalloproteinase-2 (127497-59-0) ; Matrix Metalloproteinase 2 (EC 3.4.24.24) ; Matrix Metalloproteinase 9 (EC 3.4.24.35) ; Matrix Metalloproteinase 14 (EC 3.4.24.80) ; Levodopa (46627O600J) ; Tissue Inhibitor of Metalloproteinases
    Language English
    Publishing date 2023-03-30
    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/s41598-023-32019-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Quantitative mapping of binding specificity landscapes for homologous targets by using a high-throughput method.

    Aharon, Lidan / Aharoni, Shay-Lee / Radisky, Evette S / Papo, Niv

    The Biochemical journal

    2020  Volume 477, Issue 9, Page(s) 1701–1719

    Abstract: To facilitate investigations of protein-protein interactions (PPIs), we developed a novel platform for quantitative mapping of protein binding specificity landscapes, which combines the multi-target screening of a mutagenesis library into high- and low- ... ...

    Abstract To facilitate investigations of protein-protein interactions (PPIs), we developed a novel platform for quantitative mapping of protein binding specificity landscapes, which combines the multi-target screening of a mutagenesis library into high- and low-affinity populations with sophisticated next-generation sequencing analysis. Importantly, this method generates accurate models to predict affinity and specificity values for any mutation within a protein complex, and requires only a few experimental binding affinity measurements using purified proteins for calibration. We demonstrated the utility of the approach by mapping quantitative landscapes for interactions between the N-terminal domain of the tissue inhibitor of metalloproteinase 2 (N-TIMP2) and three matrix metalloproteinases (MMPs) having homologous structures but different affinities (MMP-1, MMP-3, and MMP-14). The binding landscapes for N-TIMP2/MMP-1 and N-TIMP2/MMP-3 showed the PPIs to be almost fully optimized, with most single mutations giving a loss of affinity. In contrast, the non-optimized PPI for N-TIMP2/MMP-14 was reflected in a wide range of binding affinities, where single mutations exhibited a far more attenuated effect on the PPI. Our new platform reliably and comprehensively identified not only hot- and cold-spot residues, but also specificity-switch mutations that shape target affinity and specificity. Thus, our approach provides a methodology giving an unprecedentedly rich quantitative analysis of the binding specificity landscape, which will broaden the understanding of the mechanisms and evolutionary origins of specific PPIs and facilitate the rational design of specific inhibitors for structurally similar target proteins.
    MeSH term(s) Computational Biology/methods ; Gene Library ; High-Throughput Nucleotide Sequencing ; Matrix Metalloproteinase 1/metabolism ; Matrix Metalloproteinase 14/metabolism ; Matrix Metalloproteinase 3/metabolism ; Mutagenesis ; Mutation ; Protein Engineering/methods ; Protein Interaction Domains and Motifs ; Protein Interaction Mapping/methods ; Tissue Inhibitor of Metalloproteinase-2/chemistry ; Tissue Inhibitor of Metalloproteinase-2/genetics ; Tissue Inhibitor of Metalloproteinase-2/metabolism
    Chemical Substances Tissue Inhibitor of Metalloproteinase-2 (127497-59-0) ; MMP3 protein, human (EC 3.4.24.17) ; Matrix Metalloproteinase 3 (EC 3.4.24.17) ; MMP1 protein, human (EC 3.4.24.7) ; Matrix Metalloproteinase 1 (EC 3.4.24.7) ; MMP14 protein, human (EC 3.4.24.80) ; Matrix Metalloproteinase 14 (EC 3.4.24.80)
    Language English
    Publishing date 2020-04-13
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2969-5
    ISSN 1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
    ISSN (online) 1470-8728
    ISSN 0006-2936 ; 0306-3275 ; 0264-6021
    DOI 10.1042/BCJ20200188
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    In stock of ZB MED Cologne/Königswinter

    Uc I Zs.110: Show issues Location:
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