Fragment-based exploration of the 14-3-3/Amot-p130 interface

Federica Centorrino; Blaž Andlovic; Peter Cossar; Luc Brunsveld; Christian Ottmann

doi:10.1016/j.crstbi.2021.12.003

Fragment-based exploration of the 14-3-3/Amot-p130 interface

Federica Centorrino
, Blaž Andlovic
, Peter Cossar
, Luc Brunsveld
, Christian Ottmann (Corresponding author)

Research output: Contribution to journal › Article › Academic › peer-review

12 Citations (Scopus)

178 Downloads (Pure)

Abstract

The modulation of protein-protein interactions (PPIs) has developed into a well-established field of drug discovery. Despite the advances achieved in the field, many PPIs are still deemed as ‘undruggable’ targets and the design of PPIs stabilizers remains a significant challenge. The application of fragment-based methods for the identification of drug leads and to evaluate the ‘tractability’ of the desired protein target has seen a remarkable development in recent years. In this study, we explore the molecular characteristics of the 14-3-3/Amot-p130 PPI and the conceptual possibility of targeting this interface using X-ray crystallography fragment-based screening. We report the first structural elucidation of the 14-3-3 binding motif of Amot-p130 and the characterization of the binding mode and affinities involved. We made use of fragments to probe the ‘ligandability’ of the 14-3-3/Amot-p130 composite binding pocket. Here we disclose initial hits with promising stabilizing activity and an early-stage selectivity toward the Amot-p130 motifs over other representatives 14-3-3 partners. Our findings highlight the potential of using fragments to characterize and explore proteins' surfaces and might provide a starting point toward the development of small molecules capable of acting as molecular glues.

Original language	English
Pages (from-to)	21-28
Number of pages	8
Journal	Current Research in Structural Biology
Volume	4
DOIs	https://doi.org/10.1016/j.crstbi.2021.12.003
Publication status	Published - Jan 2022

Bibliographical note

Funding Information:
This research was supported through the Initial Training Network TASPPI, funded by the H2020 Marie Curie Actions of the European Commission under Grant Agreement 675179 and through a Eurotech Postdoctoral Fellow program (Marie Skłodowska-Curie Co-funded, grant number 754462 ). We would like to thank Dr. Hongming Chen and Helen Boyd (AstraZeneca) for providing the fragments for X-ray crystallography and initial FP validation. We thank Dr. Matthew Perry (AstraZeneca) for providing fragments 09 and 22 for MST assay and additional FP assays.

Funding

This research was supported through the Initial Training Network TASPPI, funded by the H2020 Marie Curie Actions of the European Commission under Grant Agreement 675179 and through a Eurotech Postdoctoral Fellow program (Marie Skłodowska-Curie Co-funded, grant number 754462 ). We would like to thank Dr. Hongming Chen and Helen Boyd (AstraZeneca) for providing the fragments for X-ray crystallography and initial FP validation. We thank Dr. Matthew Perry (AstraZeneca) for providing fragments 09 and 22 for MST assay and additional FP assays. This research was supported through the Initial Training Network TASPPI, funded by the H2020 Marie Curie Actions of the European Commission under Grant Agreement 675179 and through a Eurotech Postdoctoral Fellow program (Marie Sk?odowska-Curie Co-funded, grant number 754462). We would like to thank Dr. Hongming Chen and Helen Boyd (AstraZeneca) for providing the fragments for X-ray crystallography and initial FP validation. We thank Dr. Matthew Perry (AstraZeneca) for providing fragments 09 and 22 for MST assay and additional FP assays.

Keywords

14-3-3 /protein-protein interactions stabilizers
Amot-p130
Fragment-based drug discovery
Ligandability
X-ray crystallography

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10.1016/j.crstbi.2021.12.003

published versionFinal published version, 2.39 MBLicence: CC BY-NC-ND

Cite this

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title = "Fragment-based exploration of the 14-3-3/Amot-p130 interface",

abstract = "The modulation of protein-protein interactions (PPIs) has developed into a well-established field of drug discovery. Despite the advances achieved in the field, many PPIs are still deemed as {\textquoteleft}undruggable{\textquoteright} targets and the design of PPIs stabilizers remains a significant challenge. The application of fragment-based methods for the identification of drug leads and to evaluate the {\textquoteleft}tractability{\textquoteright} of the desired protein target has seen a remarkable development in recent years. In this study, we explore the molecular characteristics of the 14-3-3/Amot-p130 PPI and the conceptual possibility of targeting this interface using X-ray crystallography fragment-based screening. We report the first structural elucidation of the 14-3-3 binding motif of Amot-p130 and the characterization of the binding mode and affinities involved. We made use of fragments to probe the {\textquoteleft}ligandability{\textquoteright} of the 14-3-3/Amot-p130 composite binding pocket. Here we disclose initial hits with promising stabilizing activity and an early-stage selectivity toward the Amot-p130 motifs over other representatives 14-3-3 partners. Our findings highlight the potential of using fragments to characterize and explore proteins' surfaces and might provide a starting point toward the development of small molecules capable of acting as molecular glues.",

keywords = "14-3-3 /protein-protein interactions stabilizers, Amot-p130, Fragment-based drug discovery, Ligandability, X-ray crystallography",

author = "Federica Centorrino and Bla{\v z} Andlovic and Peter Cossar and Luc Brunsveld and Christian Ottmann",

note = "Funding Information: This research was supported through the Initial Training Network TASPPI, funded by the H2020 Marie Curie Actions of the European Commission under Grant Agreement 675179 and through a Eurotech Postdoctoral Fellow program (Marie Sk{\l}odowska-Curie Co-funded, grant number 754462 ). We would like to thank Dr. Hongming Chen and Helen Boyd (AstraZeneca) for providing the fragments for X-ray crystallography and initial FP validation. We thank Dr. Matthew Perry (AstraZeneca) for providing fragments 09 and 22 for MST assay and additional FP assays. ",

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AU - Cossar, Peter

AU - Brunsveld, Luc

AU - Ottmann, Christian

N1 - Funding Information: This research was supported through the Initial Training Network TASPPI, funded by the H2020 Marie Curie Actions of the European Commission under Grant Agreement 675179 and through a Eurotech Postdoctoral Fellow program (Marie Skłodowska-Curie Co-funded, grant number 754462 ). We would like to thank Dr. Hongming Chen and Helen Boyd (AstraZeneca) for providing the fragments for X-ray crystallography and initial FP validation. We thank Dr. Matthew Perry (AstraZeneca) for providing fragments 09 and 22 for MST assay and additional FP assays.

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N2 - The modulation of protein-protein interactions (PPIs) has developed into a well-established field of drug discovery. Despite the advances achieved in the field, many PPIs are still deemed as ‘undruggable’ targets and the design of PPIs stabilizers remains a significant challenge. The application of fragment-based methods for the identification of drug leads and to evaluate the ‘tractability’ of the desired protein target has seen a remarkable development in recent years. In this study, we explore the molecular characteristics of the 14-3-3/Amot-p130 PPI and the conceptual possibility of targeting this interface using X-ray crystallography fragment-based screening. We report the first structural elucidation of the 14-3-3 binding motif of Amot-p130 and the characterization of the binding mode and affinities involved. We made use of fragments to probe the ‘ligandability’ of the 14-3-3/Amot-p130 composite binding pocket. Here we disclose initial hits with promising stabilizing activity and an early-stage selectivity toward the Amot-p130 motifs over other representatives 14-3-3 partners. Our findings highlight the potential of using fragments to characterize and explore proteins' surfaces and might provide a starting point toward the development of small molecules capable of acting as molecular glues.

AB - The modulation of protein-protein interactions (PPIs) has developed into a well-established field of drug discovery. Despite the advances achieved in the field, many PPIs are still deemed as ‘undruggable’ targets and the design of PPIs stabilizers remains a significant challenge. The application of fragment-based methods for the identification of drug leads and to evaluate the ‘tractability’ of the desired protein target has seen a remarkable development in recent years. In this study, we explore the molecular characteristics of the 14-3-3/Amot-p130 PPI and the conceptual possibility of targeting this interface using X-ray crystallography fragment-based screening. We report the first structural elucidation of the 14-3-3 binding motif of Amot-p130 and the characterization of the binding mode and affinities involved. We made use of fragments to probe the ‘ligandability’ of the 14-3-3/Amot-p130 composite binding pocket. Here we disclose initial hits with promising stabilizing activity and an early-stage selectivity toward the Amot-p130 motifs over other representatives 14-3-3 partners. Our findings highlight the potential of using fragments to characterize and explore proteins' surfaces and might provide a starting point toward the development of small molecules capable of acting as molecular glues.

KW - 14-3-3 /protein-protein interactions stabilizers

KW - Amot-p130

KW - Fragment-based drug discovery

KW - Ligandability

KW - X-ray crystallography

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U2 - 10.1016/j.crstbi.2021.12.003

DO - 10.1016/j.crstbi.2021.12.003

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C2 - 35036934

AN - SCOPUS:85122367354

SN - 2665-928X

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SP - 21

EP - 28

JO - Current Research in Structural Biology

JF - Current Research in Structural Biology

ER -

Fragment-based exploration of the 14-3-3/Amot-p130 interface

Abstract

Bibliographical note

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Keywords

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