4gq4 - Revision history

OCA at 11:33, 1 March 2024

OCA — Fri, 01 Mar 2024 11:33:47 GMT

←Older revision		Revision as of 11:33, 1 March 2024
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	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4gq4]] 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=4GQ4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GQ4 FirstGlance]. <br>		<table><tr><td colspan='2'>[[4gq4]] 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=4GQ4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GQ4 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0RT:4-[4-(5,5-DIMETHYL-4,5-DIHYDRO-1,3-THIAZOL-2-YL)PIPERAZIN-1-YL]-6-(2,2,2-TRIFLUOROETHYL)THIENO[2,3-D]PYRIMIDINE'>0RT</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=PE4:2-{2-[2-(2-{2-[2-(2-ETHOXY-ETHOXY)-ETHOXY]-ETHOXY}-ETHOXY)-ETHOXY]-ETHOXY}-ETHANOL'>PE4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene></td></tr>	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 1.27Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0RT:4-[4-(5,5-DIMETHYL-4,5-DIHYDRO-1,3-THIAZOL-2-YL)PIPERAZIN-1-YL]-6-(2,2,2-TRIFLUOROETHYL)THIENO[2,3-D]PYRIMIDINE'>0RT</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=PE4:2-{2-[2-(2-{2-[2-(2-ETHOXY-ETHOXY)-ETHOXY]-ETHOXY}-ETHOXY)-ETHOXY]-ETHOXY}-ETHANOL'>PE4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene></td></tr>
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4gq4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gq4 OCA], [https://pdbe.org/4gq4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4gq4 RCSB], [https://www.ebi.ac.uk/pdbsum/4gq4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4gq4 ProSAT]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4gq4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gq4 OCA], [https://pdbe.org/4gq4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4gq4 RCSB], [https://www.ebi.ac.uk/pdbsum/4gq4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4gq4 ProSAT]</span></td></tr>
	</table>		</table>
Line 11:		Line 12:
	== Function ==		== Function ==
	[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>		[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>
-	<div style="background-color:#fffaf0;">
-	== Publication Abstract from PubMed ==
-	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.
-
-	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>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 4gq4" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==

OCA at 07:10, 26 October 2022

OCA — Wed, 26 Oct 2022 07:10:14 GMT

←Older revision		Revision as of 07:10, 26 October 2022
Line 1:		Line 1:

	==Human menin with bound inhibitor MI-2-2==		==Human menin with bound inhibitor MI-2-2==
-	<StructureSection load='4gq4' size='340' side='right' caption='[[4gq4]], [[Resolution\|resolution]] 1.27Å' scene=''>	+	<StructureSection load='4gq4' size='340' side='right'caption='[[4gq4]], [[Resolution\|resolution]] 1.27Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4gq4]] 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=4GQ4 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4GQ4 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4gq4]] 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=4GQ4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GQ4 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0RT:4-[4-(5,5-DIMETHYL-4,5-DIHYDRO-1,3-THIAZOL-2-YL)PIPERAZIN-1-YL]-6-(2,2,2-TRIFLUOROETHYL)THIENO[2,3-D]PYRIMIDINE'>0RT</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=PE4:2-{2-[2-(2-{2-[2-(2-ETHOXY-ETHOXY)-ETHOXY]-ETHOXY}-ETHOXY)-ETHOXY]-ETHOXY}-ETHANOL'>PE4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene>~~</td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0RT:4-[4-(5,5-DIMETHYL-4,5-DIHYDRO-1,3-THIAZOL-2-YL)PIPERAZIN-1-YL]-6-(2,2,2-TRIFLUOROETHYL)THIENO[2,3-D]PYRIMIDINE'>0RT</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=PE4:2-{2-[2-(2-{2-[2-(2-ETHOXY-ETHOXY)-ETHOXY]-ETHOXY}-ETHOXY)-ETHOXY]-ETHOXY}-ETHANOL'>PE4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene></td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4gpq\|4gpq]], [[4gq3\|4gq3]], [[4gq6\|4gq6]]</td></tr>~~	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4gq4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gq4 OCA], [https://pdbe.org/4gq4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4gq4 RCSB], [https://www.ebi.ac.uk/pdbsum/4gq4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4gq4 ProSAT]</span></td></tr>
-	~~<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>	+
-	<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=4gq4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gq4 OCA], [~~http~~://pdbe.org/4gq4 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4gq4 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4gq4 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4gq4 ProSAT]</span></td></tr>	+
	</table>		</table>
	== Disease ==		== Disease ==
-	[~~[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>	+	[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 ==
-	[~~[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>	+	[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>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 29:		Line 27:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
-	[[Category: Chruszcz, M]]	+	[[Category: Large Structures]]
-	[[Category: Cierpicki, T]]	+	[[Category: Chruszcz M]]
-	[[Category: Grembecka, J]]	+	[[Category: Cierpicki T]]
-	[[Category: Hartley, T]]	+	[[Category: Grembecka J]]
-	[[Category: He, S]]	+	[[Category: Hartley T]]
-	[[Category: Lund~~, G L~~]]	+	[[Category: He S]]
-	[[Category: Murai~~, M J~~]]	+	[[Category: Lund GL]]
-	[[Category: Purohit, T]]	+	[[Category: Murai MJ]]
-	[[Category: Reddy, G]]	+	[[Category: Purohit T]]
-	[[Category: Shi, A]]	+	[[Category: Reddy G]]
-	~~[[Category: Nucleus]]~~	+	[[Category: Shi A]]
-	~~[[Category: Transcription-transcription inhibitor complex]]~~	+
-	~~[[Category: Tumor suppressor~~]]	+

OCA at 07:51, 4 August 2016

OCA — Thu, 04 Aug 2016 07:51:45 GMT

←Older revision		Revision as of 07:51, 4 August 2016
Line 1:		Line 1:
		+
	==Human menin with bound inhibitor MI-2-2==		==Human menin with bound inhibitor MI-2-2==
	<StructureSection load='4gq4' size='340' side='right' caption='[[4gq4]], [[Resolution\|resolution]] 1.27Å' scene=''>		<StructureSection load='4gq4' size='340' side='right' caption='[[4gq4]], [[Resolution\|resolution]] 1.27Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4gq4]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Homo_sapiens Homo sapiens~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GQ4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GQ4 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4gq4]] 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=4GQ4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GQ4 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0RT:4-[4-(5,5-DIMETHYL-4,5-DIHYDRO-1,3-THIAZOL-2-YL)PIPERAZIN-1-YL]-6-(2,2,2-TRIFLUOROETHYL)THIENO[2,3-D]PYRIMIDINE'>0RT</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=PE4:2-{2-[2-(2-{2-[2-(2-ETHOXY-ETHOXY)-ETHOXY]-ETHOXY}-ETHOXY)-ETHOXY]-ETHOXY}-ETHANOL'>PE4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0RT:4-[4-(5,5-DIMETHYL-4,5-DIHYDRO-1,3-THIAZOL-2-YL)PIPERAZIN-1-YL]-6-(2,2,2-TRIFLUOROETHYL)THIENO[2,3-D]PYRIMIDINE'>0RT</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=PE4:2-{2-[2-(2-{2-[2-(2-ETHOXY-ETHOXY)-ETHOXY]-ETHOXY}-ETHOXY)-ETHOXY]-ETHOXY}-ETHANOL'>PE4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4gpq\|4gpq]], [[4gq3\|4gq3]], [[4gq6\|4gq6]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4gpq\|4gpq]], [[4gq3\|4gq3]], [[4gq6\|4gq6]]</td></tr>
-	<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 ~~Homo sapiens~~])</td></tr>	+	<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>
-	<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=4gq4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gq4 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4gq4 RCSB], [http://www.ebi.ac.uk/pdbsum/4gq4 PDBsum]</span></td></tr>	+	<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=4gq4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gq4 OCA], [http://pdbe.org/4gq4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4gq4 RCSB], [http://www.ebi.ac.uk/pdbsum/4gq4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4gq4 ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 20:		Line 21:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
		+	<div class="pdbe-citations 4gq4" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 27:		Line 29:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Homo sapiens~~]]	+	[[Category: Human]]
	[[Category: Chruszcz, M]]		[[Category: Chruszcz, M]]
	[[Category: Cierpicki, T]]		[[Category: Cierpicki, T]]

OCA at 07:13, 24 December 2014

OCA — Wed, 24 Dec 2014 07:13:54 GMT

←Older revision		Revision as of 07:13, 24 December 2014
Line 1:		Line 1:
-	[[~~Image:~~4gq4.~~png~~\|~~left~~\|~~200px~~]]	+	==Human menin with bound inhibitor MI-2-2==
		+	<StructureSection load='4gq4' size='340' side='right' caption='[[4gq4]], [[Resolution\|resolution]] 1.27Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[4gq4]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GQ4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GQ4 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0RT:4-[4-(5,5-DIMETHYL-4,5-DIHYDRO-1,3-THIAZOL-2-YL)PIPERAZIN-1-YL]-6-(2,2,2-TRIFLUOROETHYL)THIENO[2,3-D]PYRIMIDINE'>0RT</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=PE4:2-{2-[2-(2-{2-[2-(2-ETHOXY-ETHOXY)-ETHOXY]-ETHOXY}-ETHOXY)-ETHOXY]-ETHOXY}-ETHANOL'>PE4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4gpq\|4gpq]], [[4gq3\|4gq3]], [[4gq6\|4gq6]]</td></tr>
		+	<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 Homo sapiens])</td></tr>
		+	<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=4gq4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gq4 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4gq4 RCSB], [http://www.ebi.ac.uk/pdbsum/4gq4 PDBsum]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[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>
		+	== Function ==
		+	[[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>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	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.

-	~~{{STRUCTURE_4gq4\| PDB=4gq4 \| SCENE= }}~~	+	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>

-	~~===Human menin with bound inhibitor MI-2-2===~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>

-	~~{{ABSTRACT_PUBMED_22936661}}~~	+	==See Also==
-		+	*[[Menin\|Menin]]
-	==~~About this Structure~~==	+	== References ==
-	[[~~4gq4~~]] ~~is a 1 chain structure with sequence from [http:~~//~~en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GQ4 OCA].~~	+	<references/>
		+	__TOC__
		+	</StructureSection>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
-	[[Category: Chruszcz, M.]]	+	[[Category: Chruszcz, M]]
-	[[Category: Cierpicki, T.]]	+	[[Category: Cierpicki, T]]
-	[[Category: Grembecka, J.]]	+	[[Category: Grembecka, J]]
-	[[Category: Hartley, T.]]	+	[[Category: Hartley, T]]
-	[[Category: He, S.]]	+	[[Category: He, S]]
-	[[Category: Lund, G L.]]	+	[[Category: Lund, G L]]
-	[[Category: Murai, M J.]]	+	[[Category: Murai, M J]]
-	[[Category: Purohit, T.]]	+	[[Category: Purohit, T]]
-	[[Category: Reddy, G.]]	+	[[Category: Reddy, G]]
-	[[Category: Shi, A.]]	+	[[Category: Shi, A]]
	[[Category: Nucleus]]		[[Category: Nucleus]]
	[[Category: Transcription-transcription inhibitor complex]]		[[Category: Transcription-transcription inhibitor complex]]
	[[Category: Tumor suppressor]]		[[Category: Tumor suppressor]]

OCA at 15:46, 28 November 2012

OCA — Wed, 28 Nov 2012 15:46:38 GMT

←Older revision		Revision as of 15:46, 28 November 2012
Line 8:		Line 8:

	==About this Structure==		==About this Structure==
-	[[4gq4]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GQ4 OCA].	+	[[4gq4]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GQ4 OCA].
		+	[[Category: Homo sapiens]]
	[[Category: Chruszcz, M.]]		[[Category: Chruszcz, M.]]
	[[Category: Cierpicki, T.]]		[[Category: Cierpicki, T.]]

OCA at 06:34, 10 October 2012

OCA — Wed, 10 Oct 2012 06:34:41 GMT

←Older revision		Revision as of 06:34, 10 October 2012
Line 1:		Line 1:
-	[[Image:4gq4.~~jpg~~\|left\|200px]]	+	[[Image:4gq4.png\|left\|200px]]

	{{STRUCTURE_4gq4\| PDB=4gq4 \| SCENE= }}		{{STRUCTURE_4gq4\| PDB=4gq4 \| SCENE= }}
Line 8:		Line 8:

	==About this Structure==		==About this Structure==
-	[[4gq4]] is a 1 chain structure ~~with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]~~. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GQ4 OCA].	+	[[4gq4]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GQ4 OCA].
-	~~[[Category: Homo sapiens]]~~	+
	[[Category: Chruszcz, M.]]		[[Category: Chruszcz, M.]]
	[[Category: Cierpicki, T.]]		[[Category: Cierpicki, T.]]

OCA at 07:17, 19 September 2012

OCA — Wed, 19 Sep 2012 07:17:02 GMT

←Older revision		Revision as of 07:17, 19 September 2012
Line 1:		Line 1:
-	~~'''Unreleased structure'''~~	+	[[Image:4gq4.jpg\|left\|200px]]

-	~~The entry~~ 4gq4 ~~is ON HOLD~~ ~~until Paper Publication~~	+	{{STRUCTURE_4gq4\| PDB=4gq4 \| SCENE= }}

-	~~Authors: Shi, A., Murai, M.J., He, S., Lund, G.L., Hartley, T., Purohit, T., Reddy, G., Chruszcz, M., Grembecka, J., Cierpicki, T.~~	+	===Human menin with bound inhibitor MI-2-2===

-	~~Description: Human menin~~ with ~~bound inhibitor MI~~-2-2	+	{{ABSTRACT_PUBMED_22936661}}
		+
		+	==About this Structure==
		+	[[4gq4]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GQ4 OCA].
		+	[[Category: Homo sapiens]]
		+	[[Category: Chruszcz, M.]]
		+	[[Category: Cierpicki, T.]]
		+	[[Category: Grembecka, J.]]
		+	[[Category: Hartley, T.]]
		+	[[Category: He, S.]]
		+	[[Category: Lund, G L.]]
		+	[[Category: Murai, M J.]]
		+	[[Category: Purohit, T.]]
		+	[[Category: Reddy, G.]]
		+	[[Category: Shi, A.]]
		+	[[Category: Nucleus]]
		+	[[Category: Transcription-transcription inhibitor complex]]
		+	[[Category: Tumor suppressor]]

OCA at 04:52, 12 September 2012

OCA — Wed, 12 Sep 2012 04:52:31 GMT

←Older revision		Revision as of 04:52, 12 September 2012
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 4gq4 is ON HOLD	+	The entry 4gq4 is ON HOLD until Paper Publication

	Authors: Shi, A., Murai, M.J., He, S., Lund, G.L., Hartley, T., Purohit, T., Reddy, G., Chruszcz, M., Grembecka, J., Cierpicki, T.		Authors: Shi, A., Murai, M.J., He, S., Lund, G.L., Hartley, T., Purohit, T., Reddy, G., Chruszcz, M., Grembecka, J., Cierpicki, T.

	Description: Human menin with bound inhibitor MI-2-2		Description: Human menin with bound inhibitor MI-2-2

OCA: Protected "4gq4" [edit=sysop:move=sysop]

OCA — Wed, 29 Aug 2012 04:50:30 GMT

Protected "4gq4" [edit=sysop:move=sysop]

←Older revision

Revision as of 04:50, 29 August 2012

OCA: New page: '''Unreleased structure''' The entry 4gq4 is ON HOLD Authors: Shi, A., Murai, M.J., He, S., Lund, G.L., Hartley, T., Purohit, T., Reddy, G., Chruszcz, M., Grembecka, J., Cierpicki, T. ...

OCA — Wed, 29 Aug 2012 04:50:29 GMT

New page: '''Unreleased structure''' The entry 4gq4 is ON HOLD Authors: Shi, A., Murai, M.J., He, S., Lund, G.L., Hartley, T., Purohit, T., Reddy, G., Chruszcz, M., Grembecka, J., Cierpicki, T. ...

New page

'''Unreleased structure'''

The entry 4gq4 is ON HOLD

Authors: Shi, A., Murai, M.J., He, S., Lund, G.L., Hartley, T., Purohit, T., Reddy, G., Chruszcz, M., Grembecka, J., Cierpicki, T.

Description: Human menin with bound inhibitor MI-2-2