9EXW

Crystal structure of the PWWP1 domain of NSD2 bound by compound 17.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.43 Å
  • R-Value Free: 0.284 
  • R-Value Work: 0.234 
  • R-Value Observed: 0.237 

wwPDB Validation   3D Report Full Report


This is version 1.0 of the entry. See complete history


Literature

Identification of Novel Potent NSD2-PWWP1 Ligands Using Structure-Based Design and Computational Approaches.

Carlino, L.Astles, P.C.Ackroyd, B.Ahmed, A.Chan, C.Collie, G.W.Dale, I.L.O'Donovan, D.H.Fawcett, C.di Fruscia, P.Gohlke, A.Guo, X.Hao-Ru Hsu, J.Kaplan, B.Milbradt, A.G.Northall, S.Petrovic, D.Rivers, E.L.Underwood, E.Webb, A.

(2024) J Med Chem 

  • DOI: https://doi.org/10.1021/acs.jmedchem.4c00215
  • Primary Citation of Related Structures:  
    9EXW, 9EXX, 9EXY

  • PubMed Abstract: 

    Dysregulation of histone methyl transferase nuclear receptor-binding SET domain 2 (NSD2) has been implicated in several hematological and solid malignancies. NSD2 is a large multidomain protein that carries histone writing and histone reading functions. To date, identifying inhibitors of the enzymatic activity of NSD2 has proven challenging in terms of potency and SET domain selectivity. Inhibition of the NSD2-PWWP1 domain using small molecules has been considered as an alternative approach to reduce NSD2-unregulated activity. In this article, we present novel computational chemistry approaches, encompassing free energy perturbation coupled to machine learning (FEP/ML) models as well as virtual screening (VS) activities, to identify high-affinity NSD2 PWWP1 binders. Through these activities, we have identified the most potent NSD2-PWWP1 binder reported so far in the literature: compound 34 (pIC 50 = 8.2). The compounds identified herein represent useful tools for studying the role of PWWP1 domains for inhibition of human NSD2.


  • Organizational Affiliation

    Oncology R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Histone-lysine N-methyltransferase NSD2
A, B
174Homo sapiensMutation(s): 0 
Gene Names: NSD2KIAA1090MMSETTRX5WHSC1
EC: 2.1.1.357
UniProt & NIH Common Fund Data Resources
Find proteins for O96028 (Homo sapiens)
Explore O96028 
Go to UniProtKB:  O96028
PHAROS:  O96028
GTEx:  ENSG00000109685 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO96028
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
A1H7X (Subject of Investigation/LOI)
Query on A1H7X

Download Ideal Coordinates CCD File 
E [auth A],
F [auth B]
7-[3-methyl-5-[2-methyl-5-[(pyridin-3-ylamino)methyl]phenyl]imidazol-4-yl]-4~{H}-1,4-benzoxazin-3-one
C25 H23 N5 O2
APUAYMXUHLOPLQ-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.43 Å
  • R-Value Free: 0.284 
  • R-Value Work: 0.234 
  • R-Value Observed: 0.237 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 48.726α = 90
b = 55.669β = 90
c = 150.818γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
XDSdata reduction
XDSdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data

  • Released Date: 2024-05-29 
  • Deposition Author(s): Collie, G.W.

Funding OrganizationLocationGrant Number
Not funded--

Revision History  (Full details and data files)

  • Version 1.0: 2024-05-29
    Type: Initial release