4I80

Crystal structure of human menin in complex with a high-affinity macrocyclic peptidomimetics

Summary for 4I80

• Entry DOI: 10.2210/pdb4i80/pdb
• Related: 3U84 3U85 3U88
• Related PRD ID: PRD_000967
• Descriptor: Menin, macrocyclic peptidomimetic (2 entities in total)
• Functional Keywords: menin, men1, mll, macrocyclic peptidomimetic, transcription, transcription-inhibitor complex, transcription/inhibitor
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus : O00255
• Total number of polymer chains: 2
• Total formula weight: 62188.62

Authors

Huang, J.,Lei, M. (deposition date: 2012-12-01, release date: 2013-03-06, Last modification date: 2024-10-30)

Primary citation

Zhou, H.,Liu, L.,Huang, J.,Bernard, D.,Karatas, H.,Navarro, A.,Lei, M.,Wang, S.
Structure-Based Design of High-Affinity Macrocyclic Peptidomimetics to Block the Menin-Mixed Lineage Leukemia 1 (MLL1) Protein-Protein Interaction.
J.Med.Chem., 56:1113-1123, 2013

PubMed Abstract: Menin is an essential oncogenic cofactor for mixed lineage leukemia 1 (MLL1)-mediated leukemogenesis through its direct interaction with MLL1. Targeting the menin-MLL1 protein-protein interaction represents a promising strategy to block MLL1-mediated leukemogenesis. Employing a structure-based approach and starting from a linear MLL1 octapeptide, we have designed a class of potent macrocyclic peptidomimetic inhibitors of the menin-MLL1 interaction. The most potent macrocyclic peptidomimetic (MCP-1), 34, binds to menin with a K(i) value of 4.7 nM and is >600 times more potent than the corresponding acyclic peptide. Compound 34 is also less peptide-like and has a lower molecular weight than the initial MLL1 peptide. Therefore, compound 34 serves as a promising lead structure for the design of potent and cell-permeable inhibitors of the menin-MLL1 interaction.

PubMed: 23244744
DOI: 10.1021/jm3015298

Experimental method

X-RAY DIFFRACTION (3.1 Å)