Evidence map›Paper›PMID 38746206›Full record

ArticlebioRxiv : the preprint server for biology2024

Design of High Affinity Binders to Convex Protein Target Sites.

Wei Yang, Derrick R Hicks, Agnidipta Ghosh, Tristin A Schwartze, Brian Conventry, Inna Goreshnik, Aza Allen, Samer F Halabiya, Chan Johng Kim, Cynthia S Hinck and 18 more

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
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

0 citing papers in PubMed.

No citing paper in PubMed yet.

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

28 authors.

Wei YangDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Derrick R HicksDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Agnidipta GhoshDepartment of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Tristin A SchwartzeDepartment of Structural Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Brian ConventryDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Inna GoreshnikDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Aza AllenDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Samer F HalabiyaDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Chan Johng KimDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Cynthia S HinckDepartment of Structural Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
David S LeeDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Asim K BeraDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Zhe LiDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Yujia WangDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Thomas SchlichthaerleDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Longxing CaoDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Buwei HuangDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Sarah GarrettDepartment of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Stacey R GerbenDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Stephen RettieDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Piper HeineDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Analisa MurrayDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Natasha EdmanDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Lauren CarterDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Lance StewartDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Steve AlmoDepartment of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Andrew P HinckDepartment of Structural Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
David BakerDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.

Funding

Project 4: Novel reagent development to enable molecular characterizationU19AG065156 · NIA · UNIVERSITY OF WASHINGTON · PI MACCOSS, MICHAEL · 2020 to 2024
$15.9M
Designed Vehicles for Blood Brain Barrier TraversalR01AG063845 · NIA · UNIVERSITY OF WASHINGTON · PI BAKER, DAVID · 2019 to 2023
$2.5M
NIA NIH HHS R01 AG063845NIA NIH HHS U19 AG065156
6 · The paper itself

Abstract

While there has been progress in the de novo design of small globular miniproteins (50-65 residues) to bind to primarily concave regions of a target protein surface, computational design of minibinders to convex binding sites remains an outstanding challenge due to low level of overall shape complementarity. Here, we describe a general approach to generate computationally designed proteins which bind to convex target sites that employ geometrically matching concave scaffolds. We used this approach to design proteins binding to TGFβRII, CTLA-4 and PD-L1 which following experimental optimization have low nanomolar to picomolar affinities and potent biological activity. Co-crystal structures of the TGFβRII and CTLA-4 binders in complex with the receptors are in close agreement with the design models. Our approach provides a general route to generating very high affinity binders to convex protein target sites.

Identifiers

PMID38746206
PMCPMC11092582

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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.