Structural Basis and Kinetic Pathway of RBM39 Recruitment to DCAF15 by a Sulfonamide Molecular Glue E7820

Xinlin Du; Oleg A. Volkov; Robert M. Czerwinski; Hui Ling Tan; Carlos Huerta; Emily R. Morton; Jim P. Rizzi; Paul M. Wehn; Rui Xu; Deepak Nijhawan; Eli M. Wallace

doi:10.1016/j.str.2019.10.005

Structural Basis and Kinetic Pathway of RBM39 Recruitment to DCAF15 by a Sulfonamide Molecular Glue E7820

Xinlin Du, Oleg A. Volkov, Robert M. Czerwinski, Hui Ling Tan, Carlos Huerta, Emily R. Morton, Jim P. Rizzi, Paul M. Wehn, Rui Xu, Deepak Nijhawan, Eli M. Wallace

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

95 Scopus citations

Abstract

E7820 and indisulam are two examples of aryl sulfonamides that recruit RBM39 to Rbx-Cul4-DDA1-DDB1-DCAF15 E3 ligase complex, leading to its ubiquitination and degradation by the proteasome. To understand their mechanism of action, we performed kinetic analysis on the recruitment of RBM39 to DCAF15 and solved a crystal structure of DDA1-DDB1-DCAF15 in complex with E7820 and the RRM2 domain of RBM39. E7820 packs in a shallow pocket on the surface of DCAF15 and the resulting modified interface binds RBM39 through the α1 helix of the RRM2 domain. Our kinetic studies revealed that aryl sulfonamide and RBM39 bind to DCAF15 in a synergistic manner. The structural and kinetic studies confirm aryl sulfonamides as molecular glues in the recruitment of RBM39 and provide a framework for future efforts to utilize DCAF15 to degrade other proteins of interest.

Original language	English (US)
Pages (from-to)	1625-1633.e3
Journal	Structure
Volume	27
Issue number	11
DOIs	https://doi.org/10.1016/j.str.2019.10.005
State	Published - Nov 5 2019
Externally published	Yes

Keywords

DCAF15
E7820
PROTAC
RBM39
indisulam
molecular glue
sulfonamide
targeted protein degradation

ASJC Scopus subject areas

Structural Biology
Molecular Biology

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10.1016/j.str.2019.10.005

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@article{8ff1892aa1d841018ace1c07c8ab961b,

title = "Structural Basis and Kinetic Pathway of RBM39 Recruitment to DCAF15 by a Sulfonamide Molecular Glue E7820",

abstract = "E7820 and indisulam are two examples of aryl sulfonamides that recruit RBM39 to Rbx-Cul4-DDA1-DDB1-DCAF15 E3 ligase complex, leading to its ubiquitination and degradation by the proteasome. To understand their mechanism of action, we performed kinetic analysis on the recruitment of RBM39 to DCAF15 and solved a crystal structure of DDA1-DDB1-DCAF15 in complex with E7820 and the RRM2 domain of RBM39. E7820 packs in a shallow pocket on the surface of DCAF15 and the resulting modified interface binds RBM39 through the α1 helix of the RRM2 domain. Our kinetic studies revealed that aryl sulfonamide and RBM39 bind to DCAF15 in a synergistic manner. The structural and kinetic studies confirm aryl sulfonamides as molecular glues in the recruitment of RBM39 and provide a framework for future efforts to utilize DCAF15 to degrade other proteins of interest.",

keywords = "DCAF15, E7820, PROTAC, RBM39, indisulam, molecular glue, sulfonamide, targeted protein degradation",

author = "Xinlin Du and Volkov, {Oleg A.} and Czerwinski, {Robert M.} and Tan, {Hui Ling} and Carlos Huerta and Morton, {Emily R.} and Rizzi, {Jim P.} and Wehn, {Paul M.} and Rui Xu and Deepak Nijhawan and Wallace, {Eli M.}",

note = "Funding Information: This research was funded by Peloton Therapeutics , which was later acquired by Merck. X-ray diffraction data were collected at the Advanced Light Source, which is a Department of Energy (DOE) Office of Science User Facility under contract no. DE-AC02-05CH11231 and Advanced Photon Source, a DOE Office of Science User Facility operated by Argonne National Laboratory under contract no. DE-AC02-06CH11357. Publisher Copyright: {\textcopyright} 2019 Elsevier Ltd",

year = "2019",

month = nov,

day = "5",

doi = "10.1016/j.str.2019.10.005",

language = "English (US)",

volume = "27",

pages = "1625--1633.e3",

journal = "Structure",

issn = "0969-2126",

publisher = "Cell Press",

number = "11",

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TY - JOUR

T1 - Structural Basis and Kinetic Pathway of RBM39 Recruitment to DCAF15 by a Sulfonamide Molecular Glue E7820

AU - Du, Xinlin

AU - Volkov, Oleg A.

AU - Czerwinski, Robert M.

AU - Tan, Hui Ling

AU - Huerta, Carlos

AU - Morton, Emily R.

AU - Rizzi, Jim P.

AU - Wehn, Paul M.

AU - Xu, Rui

AU - Nijhawan, Deepak

AU - Wallace, Eli M.

N1 - Funding Information: This research was funded by Peloton Therapeutics , which was later acquired by Merck. X-ray diffraction data were collected at the Advanced Light Source, which is a Department of Energy (DOE) Office of Science User Facility under contract no. DE-AC02-05CH11231 and Advanced Photon Source, a DOE Office of Science User Facility operated by Argonne National Laboratory under contract no. DE-AC02-06CH11357. Publisher Copyright: © 2019 Elsevier Ltd

PY - 2019/11/5

Y1 - 2019/11/5

N2 - E7820 and indisulam are two examples of aryl sulfonamides that recruit RBM39 to Rbx-Cul4-DDA1-DDB1-DCAF15 E3 ligase complex, leading to its ubiquitination and degradation by the proteasome. To understand their mechanism of action, we performed kinetic analysis on the recruitment of RBM39 to DCAF15 and solved a crystal structure of DDA1-DDB1-DCAF15 in complex with E7820 and the RRM2 domain of RBM39. E7820 packs in a shallow pocket on the surface of DCAF15 and the resulting modified interface binds RBM39 through the α1 helix of the RRM2 domain. Our kinetic studies revealed that aryl sulfonamide and RBM39 bind to DCAF15 in a synergistic manner. The structural and kinetic studies confirm aryl sulfonamides as molecular glues in the recruitment of RBM39 and provide a framework for future efforts to utilize DCAF15 to degrade other proteins of interest.

AB - E7820 and indisulam are two examples of aryl sulfonamides that recruit RBM39 to Rbx-Cul4-DDA1-DDB1-DCAF15 E3 ligase complex, leading to its ubiquitination and degradation by the proteasome. To understand their mechanism of action, we performed kinetic analysis on the recruitment of RBM39 to DCAF15 and solved a crystal structure of DDA1-DDB1-DCAF15 in complex with E7820 and the RRM2 domain of RBM39. E7820 packs in a shallow pocket on the surface of DCAF15 and the resulting modified interface binds RBM39 through the α1 helix of the RRM2 domain. Our kinetic studies revealed that aryl sulfonamide and RBM39 bind to DCAF15 in a synergistic manner. The structural and kinetic studies confirm aryl sulfonamides as molecular glues in the recruitment of RBM39 and provide a framework for future efforts to utilize DCAF15 to degrade other proteins of interest.

KW - DCAF15

KW - E7820

KW - PROTAC

KW - RBM39

KW - indisulam

KW - molecular glue

KW - sulfonamide

KW - targeted protein degradation

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U2 - 10.1016/j.str.2019.10.005

DO - 10.1016/j.str.2019.10.005

M3 - Article

C2 - 31693911

AN - SCOPUS:85074138623

SN - 0969-2126

VL - 27

SP - 1625-1633.e3

JO - Structure

JF - Structure

IS - 11

ER -

Structural Basis and Kinetic Pathway of RBM39 Recruitment to DCAF15 by a Sulfonamide Molecular Glue E7820

Abstract

Keywords

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