Evidence map›Paper›PMID 31634471›Full record

ArticleJournal of molecular biology2020

Structural and Functional Analysis of Ubiquitin-based Inhibitors That Target the Backsides of E2 Enzymes.

Pankaj Garg, Derek F Ceccarelli, Alexander F A Keszei, Igor Kurinov, Frank Sicheri, Sachdev S Sidhu

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of molecular biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.

0numbers the graph read from it
0cells of the map it votes in
16citing papers in PubMed
1.7field-weighted citation impact, top 15% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

16 citing papers in PubMed, 33 citations in OpenAlex.

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  10. UBE2G1 Is a Critical Component of Immune Response to the Infection ofInternational journal of molecular sciences · 2022
    Article
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

6 authors at 3 institutions in 2 countries.

Pankaj GargDepartment of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada; The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada.
Derek F CeccarelliLunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.
Alexander F A KeszeiLunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.
Igor KurinovDepartment of Chemistry and Chemical Biology, NE-CAT, Cornell University, Argonne, IL 60439, USA.
Frank SicheriLunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada. Electronic address: sicheri@lunenfeld.ca.
Sachdev S SidhuDepartment of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada; The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada. Electronic address: sachdev.sidhu@utoronto.ca.
Mount Sinai Hospital · CAUniversity of Toronto · CAArgonne National Laboratory · US

Funding

User Training and OutreachP30GM124165 · NIGMS · CORNELL UNIVERSITY · PI Nozomi Ando, J Christopher Fromme · 2018 to 2026
$34.2M
Overall EvaluationP41GM103403 · NIGMS · CORNELL UNIVERSITY · PI EALICK, STEVEN E · 2012 to 2017
$14.3M
Pixel Array Detector for X-ray CrystallographyS10RR029205 · NCRR · CORNELL UNIVERSITY · PI EALICK, STEVEN E · 2010 to 2010
$1.8M
CIHR FDN143277CIHR MOP-136956NCRR NIH HHS S10 RR029205NIGMS NIH HHS P30 GM124165NIGMS NIH HHS P41 GM103403
6 · The paper itself

Abstract

Ubiquitin-conjugating E2 enzymes are central to the ubiquitination cascade and have been implicated in cancer and other diseases. Despite strong interest in developing specific E2 inhibitors, the shallow and exposed active site has proven recalcitrant to targeting with reversible small-molecule inhibitors. Here, we used phage display to generate highly potent and selective ubiquitin variants (UbVs) that target the E2 backside, which is located opposite to the active site. A UbV targeting Ube2D1 did not affect charging but greatly attenuated chain elongation. Likewise, a UbV targeting the E2 variant Ube2V1 did not interfere with the charging of its partner E2 enzyme but inhibited formation of diubiquitin. In contrast, a UbV that bound to the backside of Ube2G1 impeded the generation of thioester-linked ubiquitin to the active site cysteine of Ube2G1 by the E1 enzyme. Crystal structures of UbVs in complex with three E2 proteins revealed distinctive molecular interactions in each case, but they also highlighted a common backside pocket that the UbVs used for enhanced affinity and specificity. These findings validate the E2 backside as a target for inhibition and provide structural insights to aid inhibitor design and screening efforts.

Indexed as

Amino Acid SequenceEnzyme InhibitorsHumansPeptide LibraryProtein BindingProtein EngineeringProtein Structure, SecondaryUbiquitinUbiquitinationUbiquitin-Conjugating EnzymesEnzyme InhibitorsPeptide LibraryUbiquitinUbiquitin-Conjugating EnzymesE2 enzymesInhibitorsPhage displayProtein engineeringUbiquitin

Identifiers

PMID31634471
PMCPMC7054140
OpenAlexW2980675053

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.