Surface probing by fragment-based screening and computational methods identifies ligandable pockets on the von Hippel-Lindau (VHL) E3 ubiquitin ligase

Xavier Lucas; Inge van Molle; Alessio Ciulli

doi:10.1021/acs.jmedchem.8b00842

Surface probing by fragment-based screening and computational methods identifies ligandable pockets on the von Hippel-Lindau (VHL) E3 ubiquitin ligase

Xavier Lucas, Inge van Molle, Alessio Ciulli (Lead / Corresponding author)

Biological Chemistry and Drug Discovery

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

30 Citations (Scopus)

140 Downloads (Pure)

Abstract

Beyond the targeting of E3 ubiquitin ligases to inhibit protein homeostasis, E3 ligase binders can be repurposed as targeted protein degraders (PROTACs or molecular glues). We sought to identify new binders of the VHL E3 ligase by biophysical fragment-based screening followed by X-ray crystallographic soaking. We identified fragments binding at the ElonginC:Cullin2 interface and a new cryptic pocket in VHL, along with other potential ligandable sites predicted computationally and found to bind solvent molecules in crystal structures. The elucidated interactions provide starting points for future ligand development.

Original language	English
Pages (from-to)	7387-7393
Number of pages	7
Journal	Journal of Medicinal Chemistry
Volume	61
Issue number	16
Early online date	24 Jul 2018
DOIs	https://doi.org/10.1021/acs.jmedchem.8b00842
Publication status	Published - 23 Aug 2018

Keywords

cryptic pockets
VHL
Cullin-RING ligase
mixed-solvent molecular dynamics
ligandability
druggability
protein-protein interactions
solvent mapping
PROTAC
protein degradation
Elongin C
Chuvash polycythemia

ASJC Scopus subject areas

Drug Discovery
Molecular Medicine

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10.1021/acs.jmedchem.8b00842Licence: CC BY

Final Published VersionFinal published version, 4.46 MBLicence: CC BY

Cite this

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title = "Surface probing by fragment-based screening and computational methods identifies ligandable pockets on the von Hippel-Lindau (VHL) E3 ubiquitin ligase",

abstract = "Beyond the targeting of E3 ubiquitin ligases to inhibit protein homeostasis, E3 ligase binders can be repurposed as targeted protein degraders (PROTACs or molecular glues). We sought to identify new binders of the VHL E3 ligase by biophysical fragment-based screening followed by X-ray crystallographic soaking. We identified fragments binding at the ElonginC:Cullin2 interface and a new cryptic pocket in VHL, along with other potential ligandable sites predicted computationally and found to bind solvent molecules in crystal structures. The elucidated interactions provide starting points for future ligand development.",

keywords = "cryptic pockets, VHL, Cullin-RING ligase, mixed-solvent molecular dynamics, ligandability, druggability, protein-protein interactions, solvent mapping, PROTAC, protein degradation, Elongin C, Chuvash polycythemia",

author = "Xavier Lucas and {van Molle}, Inge and Alessio Ciulli",

note = "Funding support is gratefully acknowledged from the European Research Council (ERC-2012-StG-311460 DrugE3CRLs Starting Grant to A.C.), the European Commission (H2020-MSCA-IF2015-806323 Marie Sk{\l}odowska-Curie Actions Individual Fellowship to X.L. and EC PIEF-GA-2010-275683 Marie-Curie Intra European Fellowship to I.V.M.), and the Wellcome Trust (Strategic Awards 100476/Z/12/Z for biophysics and drug discovery and 094090/Z/10/Z for structural biology and X-ray crystallography to the Division of Biological Chemistry and Drug Discovery at Dundee).",

year = "2018",

month = aug,

day = "23",

doi = "10.1021/acs.jmedchem.8b00842",

language = "English",

volume = "61",

pages = "7387--7393",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "16",

}

Surface probing by fragment-based screening and computational methods identifies ligandable pockets on the von Hippel-Lindau (VHL) E3 ubiquitin ligase. / Lucas, Xavier; van Molle, Inge; Ciulli, Alessio (Lead / Corresponding author).
In: Journal of Medicinal Chemistry, Vol. 61, No. 16, 23.08.2018, p. 7387-7393.

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

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AU - Lucas, Xavier

AU - van Molle, Inge

AU - Ciulli, Alessio

N1 - Funding support is gratefully acknowledged from the European Research Council (ERC-2012-StG-311460 DrugE3CRLs Starting Grant to A.C.), the European Commission (H2020-MSCA-IF2015-806323 Marie Skłodowska-Curie Actions Individual Fellowship to X.L. and EC PIEF-GA-2010-275683 Marie-Curie Intra European Fellowship to I.V.M.), and the Wellcome Trust (Strategic Awards 100476/Z/12/Z for biophysics and drug discovery and 094090/Z/10/Z for structural biology and X-ray crystallography to the Division of Biological Chemistry and Drug Discovery at Dundee).

PY - 2018/8/23

Y1 - 2018/8/23

N2 - Beyond the targeting of E3 ubiquitin ligases to inhibit protein homeostasis, E3 ligase binders can be repurposed as targeted protein degraders (PROTACs or molecular glues). We sought to identify new binders of the VHL E3 ligase by biophysical fragment-based screening followed by X-ray crystallographic soaking. We identified fragments binding at the ElonginC:Cullin2 interface and a new cryptic pocket in VHL, along with other potential ligandable sites predicted computationally and found to bind solvent molecules in crystal structures. The elucidated interactions provide starting points for future ligand development.

AB - Beyond the targeting of E3 ubiquitin ligases to inhibit protein homeostasis, E3 ligase binders can be repurposed as targeted protein degraders (PROTACs or molecular glues). We sought to identify new binders of the VHL E3 ligase by biophysical fragment-based screening followed by X-ray crystallographic soaking. We identified fragments binding at the ElonginC:Cullin2 interface and a new cryptic pocket in VHL, along with other potential ligandable sites predicted computationally and found to bind solvent molecules in crystal structures. The elucidated interactions provide starting points for future ligand development.

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KW - protein degradation

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KW - Chuvash polycythemia

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Surface probing by fragment-based screening and computational methods identifies ligandable pockets on the von Hippel-Lindau (VHL) E3 ubiquitin ligase

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

DrugE3CRL's: Probing Druggability of Multisubunit Complexes: E3 Cullin RING Ligases (ERC Starting Grant)

A Translational Engine for Biomedical Discoveries (Strategic Grant)

Ciulli, Alessio

Cite this

Surface probing by fragment-based screening and computational methods identifies ligandable pockets on the von Hippel-Lindau (VHL) E3 ubiquitin ligase

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Projects

DrugE3CRL's: Probing Druggability of Multisubunit Complexes: E3 Cullin RING Ligases (ERC Starting Grant)

A Translational Engine for Biomedical Discoveries (Strategic Grant)

Profiles

Ciulli, Alessio

Cite this