4i80

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

spinqualitylabelsall models 4i80, resolution 3.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4i80 is a 2 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.1Å Ligands: 1E3, ACE Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease MEN1_HUMAN Defects in MEN1 are the cause of familial multiple endocrine neoplasia type I (MEN1) [MIM:131100. Autosomal dominant disorder characterized by tumors of the parathyroid glands, gastro-intestinal endocrine tissue, the anterior pituitary and other tissues. Cutaneous lesions and nervous-tissue tumors can exist. Prognosis in MEN1 patients is related to hormonal hypersecretion by tumors, such as hypergastrinemia causing severe peptic ulcer disease (Zollinger-Ellison syndrome, ZES), primary hyperparathyroidism, and acute forms of hyperinsulinemia. Defects in MEN1 are the cause of familial isolated hyperparathyroidism (FIHP) [MIM:145000; also known as hyperparathyroidism type 1 (HRPT1). FIHP is an autosomal dominant disorder characterized by hypercalcemia, elevated parathyroid hormone (PTH) levels, and uniglandular or multiglandular parathyroid tumors. Function MEN1_HUMAN Essential component of a MLL/SET1 histone methyltransferase (HMT) complex, a complex that specifically methylates 'Lys-4' of histone H3 (H3K4). Functions as a transcriptional regulator. Binds to the TERT promoter and represses telomerase expression. Plays a role in TGFB1-mediated inhibition of cell-proliferation, possibly regulating SMAD3 transcriptional activity. Represses JUND-mediated transcriptional activation on AP1 sites, as well as that mediated by NFKB subunit RELA. Positively regulates HOXC8 and HOXC6 gene expression. May be involved in normal hematopoiesis through the activation of HOXA9 expression (By similarity). May be involved in DNA repair. Publication Abstract from PubMed 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. Structure-Based Design of High-Affinity Macrocyclic Peptidomimetics to Block the Menin-Mixed Lineage Leukemia 1 (MLL1) Protein-Protein Interaction.,Zhou H, Liu L, Huang J, Bernard D, Karatas H, Navarro A, Lei M, Wang S J Med Chem. 2013 Feb 14;56(3):1113-23. doi: 10.1021/jm3015298. Epub 2013 Jan 17. PMID:23244744 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Menin

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