4gpq

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==Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia==
==Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia==
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<StructureSection load='4gpq' size='340' side='right' caption='[[4gpq]], [[Resolution|resolution]] 1.46&Aring;' scene=''>
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<StructureSection load='4gpq' size='340' side='right'caption='[[4gpq]], [[Resolution|resolution]] 1.46&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4gpq]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GPQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GPQ FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4gpq]] is a 1 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=4GPQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GPQ FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene></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]] 1.46&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4gq3|4gq3]], [[4gq4|4gq4]], [[4gq6|4gq6]]</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=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MEN1, SCG2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4gpq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gpq OCA], [https://pdbe.org/4gpq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4gpq RCSB], [https://www.ebi.ac.uk/pdbsum/4gpq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4gpq ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4gpq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gpq OCA], [http://pdbe.org/4gpq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4gpq RCSB], [http://www.ebi.ac.uk/pdbsum/4gpq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4gpq ProSAT]</span></td></tr>
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</table>
</table>
== Disease ==
== Disease ==
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[[http://www.uniprot.org/uniprot/MEN1_HUMAN MEN1_HUMAN]] Defects in MEN1 are the cause of familial multiple endocrine neoplasia type I (MEN1) [MIM:[http://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:[http://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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[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>
== Function ==
== Function ==
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[[http://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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[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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Menin functions as a critical oncogenic co-factor of Mixed Lineage Leukemia (MLL) fusion proteins in development of acute leukemias, and inhibition of the menin interaction with MLL fusion proteins represents a very promising strategy to reverse their oncogenic activity. MLL interacts with menin in a bivalent mode involving two N-terminal fragments of MLL. Here, we report the first high resolution crystal structure of human menin in complex with a small molecule inhibitor of the menin-MLL interaction, MI-2. The structure reveals that the compound binds to the MLL pocket in menin and mimics the key interactions of MLL with menin. Based on the menin-MI-2 structure, we developed MI-2-2, a compound that binds to menin with low nanomolar affinity (K(d) = 22 nM) and very effectively disrupts the bivalent protein-protein interaction between menin and MLL. MI-2-2 demonstrated specific and very pronounced activity in MLL leukemia cells, including inhibition of cell proliferation, downregulation of Hoxa9 expression and differentiation. Together, our results provide the rational and essential structural basis to design next generation of inhibitors for effective targeting the menin-MLL interaction in leukemia and demonstrate a proof of concept that inhibition of complex multivalent protein-protein interactions can be achieved by a small molecule inhibitor.
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Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia.,Shi A, Murai MJ, He S, Lund G, Hartley T, Purohit T, Reddy G, Chruszcz M, Grembecka J, Cierpicki T Blood. 2012 Aug 30. PMID:22936661<ref>PMID:22936661</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 4gpq" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
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[[Category: Chruszcz, M]]
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[[Category: Large Structures]]
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[[Category: Cierpicki, T]]
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[[Category: Chruszcz M]]
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[[Category: Grembecka, J]]
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[[Category: Cierpicki T]]
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[[Category: Hartley, T]]
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[[Category: Grembecka J]]
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[[Category: He, S]]
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[[Category: Hartley T]]
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[[Category: Lund, G L]]
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[[Category: He S]]
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[[Category: Murai, M J]]
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[[Category: Lund GL]]
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[[Category: Purohit, T]]
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[[Category: Murai MJ]]
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[[Category: Reddy, G]]
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[[Category: Purohit T]]
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[[Category: Shi, A]]
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[[Category: Reddy G]]
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[[Category: Nucleus]]
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[[Category: Shi A]]
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[[Category: Transcription]]
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[[Category: Tumor suppressor]]
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Current revision

Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia

PDB ID 4gpq

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