9EXW
Crystal structure of the PWWP1 domain of NSD2 bound by compound 17.
This is a non-PDB format compatible entry.
Summary for 9EXW
| Entry DOI | 10.2210/pdb9exw/pdb |
| Descriptor | Histone-lysine N-methyltransferase NSD2, 1,2-ETHANEDIOL, 7-[3-methyl-5-[2-methyl-5-[(pyridin-3-ylamino)methyl]phenyl]imidazol-4-yl]-4~{H}-1,4-benzoxazin-3-one, ... (4 entities in total) |
| Functional Keywords | methyl transferase, inhibitor, cancer drug discovery, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 39931.53 |
| Authors | Collie, G.W. (deposition date: 2024-04-09, release date: 2024-05-29, Last modification date: 2024-06-19) |
| Primary citation | 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. Identification of Novel Potent NSD2-PWWP1 Ligands Using Structure-Based Design and Computational Approaches. J.Med.Chem., 67:8962-8987, 2024 Cited by 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 (pIC = 8.2). The compounds identified herein represent useful tools for studying the role of PWWP1 domains for inhibition of human NSD2. PubMed: 38748070DOI: 10.1021/acs.jmedchem.4c00215 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.43 Å) |
Structure validation
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