6opj

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Current revision (07:14, 11 October 2023) (edit) (undo)
 
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====
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==Menin in complex with peptide inhibitor 25==
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<StructureSection load='6opj' size='340' side='right'caption='[[6opj]]' scene=''>
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<StructureSection load='6opj' size='340' side='right'caption='[[6opj]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6opj]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6OPJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6OPJ FirstGlance]. <br>
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</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6opj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6opj OCA], [http://pdbe.org/6opj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6opj RCSB], [http://www.ebi.ac.uk/pdbsum/6opj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6opj ProSAT]</span></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.5006572&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=192:1-AMINOCYCLOBUTANECARBOXLIC+ACID'>192</scene>, <scene name='pdbligand=ABA:ALPHA-AMINOBUTYRIC+ACID'>ABA</scene>, <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=N0A:3-fluoro-L-phenylalanine'>N0A</scene>, <scene name='pdbligand=ORN:L-ORNITHINE'>ORN</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6opj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6opj OCA], [https://pdbe.org/6opj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6opj RCSB], [https://www.ebi.ac.uk/pdbsum/6opj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6opj ProSAT]</span></td></tr>
</table>
</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/MEN1_HUMAN MEN1_HUMAN] Defects in MEN1 are the cause of familial multiple endocrine neoplasia type I (MEN1) [MIM:[https://omim.org/entry/131100 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.<ref>PMID:14992727</ref> <ref>PMID:9989505</ref> <ref>PMID:9103196</ref> <ref>PMID:17555499</ref> <ref>PMID:9215689</ref> <ref>PMID:9215690</ref> <ref>PMID:9463336</ref> <ref>PMID:9683585</ref> <ref>PMID:9820618</ref> <ref>PMID:9671267</ref> <ref>PMID:10660339</ref> <ref>PMID:9506756</ref> <ref>PMID:9709921</ref> <ref>PMID:9709976</ref> <ref>PMID:9709985</ref> <ref>PMID:9740255</ref> <ref>PMID:9747036</ref> <ref>PMID:9832038</ref> <ref>PMID:10617276</ref> <ref>PMID:10229909</ref> <ref>PMID:10576763</ref> <ref>PMID:9888389</ref> <ref>PMID:10090472</ref> <ref>PMID:10534569</ref> <ref>PMID:10993647</ref> <ref>PMID:10849016</ref> <ref>PMID:10664520</ref> <ref>PMID:11102994</ref> <ref>PMID:11134142</ref> <ref>PMID:11241849</ref> <ref>PMID:12112656</ref> <ref>PMID:12417605</ref> <ref>PMID:12050235</ref> <ref>PMID:12699448</ref> <ref>PMID:12791038</ref> <ref>PMID:12652570</ref> <ref>PMID:14686752</ref> <ref>PMID:12746426</ref> <ref>PMID:15730416</ref> <ref>PMID:15714081</ref> Defects in MEN1 are the cause of familial isolated hyperparathyroidism (FIHP) [MIM:[https://omim.org/entry/145000 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.<ref>PMID:9888389</ref> <ref>PMID:12699448</ref> <ref>PMID:9792884</ref> <ref>PMID:9843042</ref> <ref>PMID:10664521</ref> <ref>PMID:10634381</ref> <ref>PMID:12016470</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/MEN1_HUMAN 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.<ref>PMID:11526476</ref> <ref>PMID:11274402</ref> <ref>PMID:12874027</ref> <ref>PMID:12837246</ref> <ref>PMID:14992727</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The interaction between menin and mixed lineage leukemia (MLL) was identified as an interesting target for treating some cancers including acute leukemia. On the basis of the known crystal structure of the MBM1-menin complex (MBM - menin binding motif), several cyclic peptides were designed. Elaboration of the effective cyclization strategy using a metathesis reaction allowed for a successfully large number of derivatives to be obtained. Subsequent optimization of the loop size, as well as N-terminal, central and C-terminal parts of the studied peptides resulted in structures exhibiting low nanomolar activities. A crystal structure of an inhibitor-menin complex revealed a compact conformation of the ligand molecule, which is stabilized not only by the introduction of a covalent linker but also three intramolecular hydrogen bonds. The inhibitor adopts a figure eight-like conformation, which perfectly fits the cleft of menin. We demonstrated that the development of compact, miniprotein-like structures is a highly effective approach for inhibition of protein-protein interactions.
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Covalent and noncovalent constraints yield a figure eight-like conformation of a peptide inhibiting the menin-MLL interaction.,Fortuna P, Linhares BM, Purohit T, Pollock J, Cierpicki T, Grembecka J, Berlicki L Eur J Med Chem. 2020 Aug 20;207:112748. doi: 10.1016/j.ejmech.2020.112748. PMID:32882610<ref>PMID:32882610</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 6opj" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Menin|Menin]]
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Z-disk]]
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[[Category: Berlicki L]]
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[[Category: Cierpicki T]]
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[[Category: Fortuna P]]
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[[Category: Grembecka J]]
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[[Category: Linhares BM]]

Current revision

Menin in complex with peptide inhibitor 25

PDB ID 6opj

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