7UOA

MAGEA4-MTP1 linear peptide complex

Summary for 7UOA

• Entry DOI: 10.2210/pdb7uoa/pdb
• Descriptor: Melanoma antigen A 4, MTP-1, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: mage homology domain mhd, protein binding
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 26543.23

Authors

Williams, R.S.,Tumbale, P.S. (deposition date: 2022-04-12, release date: 2022-09-07, Last modification date: 2023-10-18)

Primary citation

Fleming, M.C.,Chiou, L.F.,Tumbale, P.P.,Droby, G.N.,Lim, J.,Norris-Drouin, J.L.,Williams, J.G.,Pearce, K.H.,Williams, R.S.,Vaziri, C.,Bowers, A.A.
Discovery and Structural Basis of the Selectivity of Potent Cyclic Peptide Inhibitors of MAGE-A4.
J.Med.Chem., 65:7231-7245, 2022

PubMed Abstract: MAGE proteins are cancer testis antigens (CTAs) that are characterized by highly conserved MAGE homology domains (MHDs) and are increasingly being found to play pivotal roles in promoting aggressive cancer types. MAGE-A4, in particular, increases DNA damage tolerance and chemoresistance in a variety of cancers by stabilizing the E3-ligase RAD18 and promoting trans-lesion synthesis (TLS). Inhibition of the MAGE-A4:RAD18 axis could sensitize cancer cells to chemotherapeutics like platinating agents. We use an mRNA display of thioether cyclized peptides to identify a series of potent and highly selective macrocyclic inhibitors of the MAGE-A4:RAD18 interaction. Co-crystal structure indicates that these inhibitors bind in a pocket that is conserved across MHDs but take advantage of A4-specific residues to achieve high isoform selectivity. Cumulatively, our data represent the first reported inhibitor of the MAGE-A4:RAD18 interaction and establish biochemical tools and structural insights for the future development of MAGE-A4-targeted cellular probes.

PubMed: 35522528
DOI: 10.1021/acs.jmedchem.2c00185

Experimental method

X-RAY DIFFRACTION (3.5 Å)