Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Nature communications, 2022-10, Vol.13 (1), p.5884-24, Article 5884

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.