Predicting the structural basis of targeted protein degradation by integrating molecular dynamics simulations with structural mass spectrometry

Tom Dixon, Derek MacPherson, Barmak Mostofian, Taras Dauzhenka, Samuel Lotz, Dwight McGee, Sharon Shechter, Utsab R. Shrestha, Rafal Wiewiora, Zachary A. McDargh, Fen Pei, Rajat Pal, João V. Ribeiro, Tanner Wilkerson, Vipin Sachdeva, Ning Gao, Shourya Jain, Samuel Sparks, Yunxing Li, Alexander Vinitsky, Xin Zhang, Asghar M. Razavi, István Kolossváry, Jason Imbriglio, Artem Evdokimov, Louise Bergeron, Wenchang Zhou, Jagat Adhikari, Benjamin Ruprecht, Alex Dickson (), Huafeng Xu (), Woody Sherman () and Jesus A. Izaguirre ()
Additional contact information
Tom Dixon: Roivant Discovery
Derek MacPherson: Roivant Discovery
Barmak Mostofian: Roivant Discovery
Taras Dauzhenka: Roivant Discovery
Samuel Lotz: Roivant Discovery
Dwight McGee: Roivant Discovery
Sharon Shechter: Roivant Discovery
Utsab R. Shrestha: Roivant Discovery
Rafal Wiewiora: Roivant Discovery
Zachary A. McDargh: Roivant Discovery
Fen Pei: Roivant Discovery
Rajat Pal: Roivant Discovery
João V. Ribeiro: Roivant Discovery
Tanner Wilkerson: Roivant Discovery
Vipin Sachdeva: Roivant Discovery
Ning Gao: Roivant Discovery
Shourya Jain: Roivant Discovery
Samuel Sparks: Roivant Discovery
Yunxing Li: Roivant Discovery
Alexander Vinitsky: Roivant Discovery
Xin Zhang: Roivant Discovery
Asghar M. Razavi: Roivant Discovery
István Kolossváry: Roivant Discovery
Jason Imbriglio: Roivant Discovery
Artem Evdokimov: Roivant Discovery
Louise Bergeron: Roivant Discovery
Wenchang Zhou: Roivant Discovery
Jagat Adhikari: Roivant Discovery
Benjamin Ruprecht: Roivant Discovery
Alex Dickson: Michigan State University
Huafeng Xu: Roivant Discovery
Woody Sherman: Roivant Discovery
Jesus A. Izaguirre: Roivant Discovery

Nature Communications, 2022, vol. 13, issue 1, 1-24

Abstract: Abstract Targeted protein degradation (TPD) is a promising approach in drug discovery for degrading proteins implicated in diseases. A key step in this process is the formation of a ternary complex where a heterobifunctional molecule induces proximity of an E3 ligase to a protein of interest (POI), thus facilitating ubiquitin transfer to the POI. In this work, we characterize 3 steps in the TPD process. (1) We simulate the ternary complex formation of SMARCA2 bromodomain and VHL E3 ligase by combining hydrogen-deuterium exchange mass spectrometry with weighted ensemble molecular dynamics (MD). (2) We characterize the conformational heterogeneity of the ternary complex using Hamiltonian replica exchange simulations and small-angle X-ray scattering. (3) We assess the ubiquitination of the POI in the context of the full Cullin-RING Ligase, confirming experimental ubiquitinomics results. Differences in degradation efficiency can be explained by the proximity of lysine residues on the POI relative to ubiquitin.

Date: 2022
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DOI: 10.1038/s41467-022-33575-4

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