7ZUU

HUMAN PRMT5:MEP50 Crystal Structure With MTA and Fragment Bound

Summary for 7ZUU

• Entry DOI: 10.2210/pdb7zuu/pdb
• Descriptor: Protein arginine N-methyltransferase 5, Methylosome protein 50, 5'-DEOXY-5'-METHYLTHIOADENOSINE, ... (6 entities in total)
• Functional Keywords: mtap, methyl transferase, fragment-based lead discovery, fbdd, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 112550.13

Authors

Ahmad, M.U.,Koelmel, W.,Arkhipova, V.,Lawson, J.D.,Smith, C.R.,Gunn, R.J. (deposition date: 2022-05-13, release date: 2022-10-19, Last modification date: 2024-10-16)

Primary citation

Smith, C.R.,Kulyk, S.,Ahmad, M.U.D.,Arkhipova, V.,Christensen, J.G.,Gunn, R.J.,Ivetac, A.,Ketcham, J.M.,Kuehler, J.,Lawson, J.D.,Thomas, N.C.,Wang, X.,Marx, M.A.
Fragment optimization and elaboration strategies - the discovery of two lead series of PRMT5/MTA inhibitors from five fragment hits.
Rsc Med Chem, 13:1549-1564, 2022

PubMed Abstract: Here we describe the early stages of a fragment-based lead discovery (FBLD) project for a recently elucidated synthetic lethal target, the PRMT5/MTA complex, for the treatment of -deleted cancers. Starting with five fragment/PRMT5/MTA X-ray co-crystal structures, we employed a two-phase fragment elaboration process encompassing optimization of fragment hits and subsequent fragment growth to increase potency, assess synthetic tractability, and enable structure-based drug design. Two lead series were identified, one of which led to the discovery of the clinical candidate MRTX1719.

PubMed: 36545438
DOI: 10.1039/d2md00163b

Experimental method

X-RAY DIFFRACTION (2.09 Å)