4N5T

The 1.7A Crystal Structure of MDMX with a Stapled Peptide, ATSP-7041

Summary for 4N5T

• Entry DOI: 10.2210/pdb4n5t/pdb
• Related PRD ID: PRD_001189
• Descriptor: Protein Mdm4, ATSP-7041 stapled-peptide (3 entities in total)
• Functional Keywords: mdm4, p53, apoptosis, cell cycle, p53 antagonist, nucleus, cell cycle-cell cycle inhibitor complex, cell cycle/cell cycle inhibitor
• Biological source: Danio rerio (leopard danio, zebra danio, zebra fish); More
• Cellular location: Nucleus : Q7ZUW7
• Total number of polymer chains: 2
• Total formula weight: 12056.12

Authors

Graves, B.J.,Lukacs, C.,Janson, C.A. (deposition date: 2013-10-10, release date: 2013-11-20, Last modification date: 2023-11-15)

Primary citation

Chang, Y.S.,Graves, B.,Guerlavais, V.,Tovar, C.,Packman, K.,To, K.H.,Olson, K.A.,Kesavan, K.,Gangurde, P.,Mukherjee, A.,Baker, T.,Darlak, K.,Elkin, C.,Filipovic, Z.,Qureshi, F.Z.,Cai, H.,Berry, P.,Feyfant, E.,Shi, X.E.,Horstick, J.,Annis, D.A.,Manning, A.M.,Fotouhi, N.,Nash, H.,Vassilev, L.T.,Sawyer, T.K.
Stapled alpha-helical peptide drug development: a potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy.
Proc.Natl.Acad.Sci.USA, 110:E3445-E3454, 2013

PubMed Abstract: Stapled α-helical peptides have emerged as a promising new modality for a wide range of therapeutic targets. Here, we report a potent and selective dual inhibitor of MDM2 and MDMX, ATSP-7041, which effectively activates the p53 pathway in tumors in vitro and in vivo. Specifically, ATSP-7041 binds both MDM2 and MDMX with nanomolar affinities, shows submicromolar cellular activities in cancer cell lines in the presence of serum, and demonstrates highly specific, on-target mechanism of action. A high resolution (1.7-Å) X-ray crystal structure reveals its molecular interactions with the target protein MDMX, including multiple contacts with key amino acids as well as a role for the hydrocarbon staple itself in target engagement. Most importantly, ATSP-7041 demonstrates robust p53-dependent tumor growth suppression in MDM2/MDMX-overexpressing xenograft cancer models, with a high correlation to on-target pharmacodynamic activity, and possesses favorable pharmacokinetic and tissue distribution properties. Overall, ATSP-7041 demonstrates in vitro and in vivo proof-of-concept that stapled peptides can be developed as therapeutically relevant inhibitors of protein-protein interaction and may offer a viable modality for cancer therapy.

PubMed: 23946421
DOI: 10.1073/pnas.1303002110

Experimental method

X-RAY DIFFRACTION (1.7 Å)