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

Dixon T, MacPherson D, Mostofian B, Dauzhenka T, Lotz S, McGee D, Shechter S, Shrestha UR, Wiewiora R, McDargh ZA, Pei F, Pal R, Ribeiro JV, Wilkerson T, Sachdeva V, Gao N, Jain S, Sparks S, Li Y, Vinitsky A, Zhang X, Razavi AM, Kolossváry I, Imbriglio J, Evdokimov A, Bergeron L, Zhou W, Adhikari J, Ruprecht B, Dickson A, Xu H, Sherman W, Izaguirre JA, Nat Commun 13(1):5884 (2022) Europe PMC

SASDPF8 – SMARCA2 bromodomain (isoform2):Protac (ACBI1):VCB (VHL-elongin C-elongin B)

von Hippel-Lindau disease tumor suppressor
Elongin-B
Elongin-C
ACBI1 protac
Probable global transcription activator SNF2L2 (isoform 2)
MWexperimental 57 kDa
MWexpected 56 kDa
VPorod 75 nm3
log I(s) 1.87×10-2 1.87×10-3 1.87×10-4 1.87×10-5
von Hippel-Lindau disease tumor suppressor Elongin-B Elongin-C ACBI1 protac Probable global transcription activator SNF2L2 (isoform 2) small angle scattering data  s, nm-1
ln I(s)
von Hippel-Lindau disease tumor suppressor Elongin-B Elongin-C ACBI1 protac Probable global transcription activator SNF2L2 (isoform 2) Guinier plot ln 1.88×10-2 Rg: 3.2 nm 0 (3.2 nm)-2 s2
(sRg)2I(s)/I(0)
von Hippel-Lindau disease tumor suppressor Elongin-B Elongin-C ACBI1 protac Probable global transcription activator SNF2L2 (isoform 2) Kratky plot 1.104 0 3 sRg
p(r)
von Hippel-Lindau disease tumor suppressor Elongin-B Elongin-C ACBI1 protac Probable global transcription activator SNF2L2 (isoform 2) pair distance distribution function Rg: 3.4 nm 0 Dmax: 11.1 nm

Data validation


There are no models related to this curve.

SAXS data from solutions of SMARCA2 bromodomain (isoform2):Protac (ACBI1):VCB (VHL-elongin C-elongin B) in 20 mM HEPES, 150 mM NaCl, 1 mM DTT, pH 7.5 were collected using a Xenocs BioXolver L with MetalJet instrument (Département de Biochimie, Université de Montréal) equipped with a Pilatus3 R 300K detector at a sample-detector distance of 0.6 m and at a wavelength of λ = 0.134 nm (I(s) vs s, where s = 4πsinθ/λ, and 2θ is the scattering angle). In-line size-exclusion chromatography (SEC) SAS was employed. The SEC parameters were as follows: A 500.00 μl sample at 16.1 mg/ml was injected at a 0.05 ml/min flow rate onto a GE Superdex 200 10/300 column at 20°C. 12 successive 60 second frames were collected. The data were normalized to the intensity of the transmitted beam and radially averaged; the scattering of the solvent-blank was subtracted.

Notes: Protac (ACBI1) is a proteolysis-targeting chimera; https://pubchem.ncbi.nlm.nih.gov/compound/137628619

von Hippel-Lindau disease tumor suppressor (VHL)
Mol. type   Protein
Organism   Homo sapiens
Olig. state   Monomer
Mon. MW   18.7 kDa
 
UniProt   P40337 (54-213)
Sequence   FASTA
 
Elongin-B (EloB)
Mol. type   Protein
Organism   Homo sapiens
Olig. state   Monomer
Mon. MW   11.7 kDa
 
UniProt   Q15370 (1-104)
Sequence   FASTA
 
Elongin-C (EloC)
Mol. type   Protein
Organism   Homo sapiens
Olig. state   Monomer
Mon. MW   10.8 kDa
 
UniProt   Q15369 (17-112)
Sequence   FASTA
 
ACBI1 protac (ACBI1)
Mol. type   Other
Olig. state   Monomer
Mon. MW   0.9 kDa
Chemical formula
 
Probable global transcription activator SNF2L2 (isoform 2) (SMARCA2 isoform2)
Mol. type   Protein
Organism   Homo sapiens
Olig. state   Monomer
Mon. MW   14.2 kDa
 
UniProt   P51531 (1373-1511)
Sequence   FASTA