5vkc - Revision history

OCA at 14:10, 13 March 2024

OCA — Wed, 13 Mar 2024 14:10:52 GMT

←Older revision		Revision as of 14:10, 13 March 2024
Line 1:		Line 1:

	==Crystal structure of MCL-1 in complex with a BIM competitive inhibitor==		==Crystal structure of MCL-1 in complex with a BIM competitive inhibitor==
-	<StructureSection load='5vkc' size='340' side='right' caption='[[5vkc]], [[Resolution\|resolution]] 2.31Å' scene=''>	+	<StructureSection load='5vkc' size='340' side='right'caption='[[5vkc]], [[Resolution\|resolution]] 2.31Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5vkc]] is a 2 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=5VKC OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5VKC FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5vkc]] 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=5VKC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5VKC FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9EA:7-(3-{[4-(4-ACETYLPIPERAZIN-1-YL)PHENOXY]METHYL}-1,5-DIMETHYL-1H-PYRAZOL-4-YL)-3-{3-[(NAPHTHALEN-1-YL)OXY]PROPYL}-1-[(PYRIDIN-3-YL)METHYL]-1H-INDOLE-2-CARBOXYLIC+ACID'>9EA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 2.31Å</td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">MCL1, BCL2L3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])~~</td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9EA:7-(3-{[4-(4-ACETYLPIPERAZIN-1-YL)PHENOXY]METHYL}-1,5-DIMETHYL-1H-PYRAZOL-4-YL)-3-{3-[(NAPHTHALEN-1-YL)OXY]PROPYL}-1-[(PYRIDIN-3-YL)METHYL]-1H-INDOLE-2-CARBOXYLIC+ACID'>9EA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=5vkc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vkc OCA], [~~http~~://pdbe.org/5vkc PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5vkc RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5vkc PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5vkc 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=5vkc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vkc OCA], [https://pdbe.org/5vkc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5vkc RCSB], [https://www.ebi.ac.uk/pdbsum/5vkc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5vkc ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/MCL1_HUMAN MCL1_HUMAN]] Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis.<ref>PMID:10766760</ref>	+	[https://www.uniprot.org/uniprot/MCL1_HUMAN MCL1_HUMAN] Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis.<ref>PMID:10766760</ref>
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	Myeloid cell leukemia 1 (MCL-1) is a BCL-2 family protein that has been implicated in the progression and survival of multiple tumor types. Herein we report a series of MCL-1 inhibitors that emanated from a high throughput screening (HTS) hit and progressed via iterative cycles of structure-guided design. Advanced compounds from this series exhibited subnanomolar affinity for MCL-1 and excellent selectivity over other BCL-2 family proteins as well as multiple kinases and GPCRs. In a MCL-1 dependent human tumor cell line, administration of compound 30b rapidly induced caspase activation with associated loss in cell viability. The small molecules described herein thus comprise effective tools for studying MCL-1 biology.	+

-	Structure-guided design of a series of MCL-1 inhibitors with high affinity and selectivity.,Bruncko M, Wang L, Sheppard GS, Phillips DC, Tahir SK, Xue J, Erickson S, Fidanze S, Fry E, Hasvold L, Jenkins GJ, Jin S, Judge RA, Kovar PJ, Madar D, Nimmer P, Park C, Petros AM, Rosenberg SH, Smith ML, Song X, Sun C, Tao ZF, Wang X, Xiao Y, Zhang H, Tse C, Leverson JD, Elmore SW, Souers AJ J Med Chem. 2015 Mar 12;58(5):2180-94. doi: 10.1021/jm501258m. Epub 2015 Feb 26. PMID:25679114<ref>PMID:25679114</ref>	+	==See Also==
-		+	*[[B-cell lymphoma proteins 3D structures\|B-cell lymphoma proteins 3D structures]]
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe~~-~~citations 5vkc" style="background~~-~~color:#fffaf0;"></div>~~	+
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
-	[[Category: ~~Judge, R A~~]]	+	[[Category: Large Structures]]
-	[[Category: ~~Souers, A J~~]]	+	[[Category: Judge RA]]
-	[[Category: ~~Mcl-1]]~~	+	[[Category: Souers AJ]]
-	~~[[Category: Signaling protein-inhibitor complex~~]]	+

OCA at 23:30, 15 November 2017

OCA — Wed, 15 Nov 2017 23:30:01 GMT

←Older revision		Revision as of 23:30, 15 November 2017
Line 3:		Line 3:
	<StructureSection load='5vkc' size='340' side='right' caption='[[5vkc]], [[Resolution\|resolution]] 2.31Å' scene=''>		<StructureSection load='5vkc' size='340' side='right' caption='[[5vkc]], [[Resolution\|resolution]] 2.31Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5vkc]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5VKC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5VKC FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5vkc]] is a 2 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=5VKC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5VKC FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9EA:7-(3-{[4-(4-ACETYLPIPERAZIN-1-YL)PHENOXY]METHYL}-1,5-DIMETHYL-1H-PYRAZOL-4-YL)-3-{3-[(NAPHTHALEN-1-YL)OXY]PROPYL}-1-[(PYRIDIN-3-YL)METHYL]-1H-INDOLE-2-CARBOXYLIC+ACID'>9EA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9EA:7-(3-{[4-(4-ACETYLPIPERAZIN-1-YL)PHENOXY]METHYL}-1,5-DIMETHYL-1H-PYRAZOL-4-YL)-3-{3-[(NAPHTHALEN-1-YL)OXY]PROPYL}-1-[(PYRIDIN-3-YL)METHYL]-1H-INDOLE-2-CARBOXYLIC+ACID'>9EA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">MCL1, BCL2L3 ([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=5vkc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vkc OCA], [http://pdbe.org/5vkc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5vkc RCSB], [http://www.ebi.ac.uk/pdbsum/5vkc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5vkc ProSAT]</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=5vkc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vkc OCA], [http://pdbe.org/5vkc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5vkc RCSB], [http://www.ebi.ac.uk/pdbsum/5vkc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5vkc ProSAT]</span></td></tr>
	</table>		</table>
Line 22:		Line 23:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Judge, R A]]		[[Category: Judge, R A]]
	[[Category: Souers, A J]]		[[Category: Souers, A J]]
	[[Category: Mcl-1]]		[[Category: Mcl-1]]
	[[Category: Signaling protein-inhibitor complex]]		[[Category: Signaling protein-inhibitor complex]]

OCA: Protected "5vkc" [edit=sysop:move=sysop]

OCA — Thu, 04 May 2017 12:59:44 GMT

Protected "5vkc" [edit=sysop:move=sysop]

←Older revision

Revision as of 12:59, 4 May 2017

OCA: New page: ==Crystal structure of MCL-1 in complex with a BIM competitive inhibitor==
OCA — Thu, 04 May 2017 12:59:41 GMT

New page: ==Crystal structure of MCL-1 in complex with a BIM competitive inhibitor== <StructureSection load='5vkc' size='340' side='right' caption='5vkc, resolution 2.31Å' ...

New page

==Crystal structure of MCL-1 in complex with a BIM competitive inhibitor==
<StructureSection load='5vkc' size='340' side='right' caption='[[5vkc]], [[Resolution|resolution]] 2.31Å' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5vkc]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5VKC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5VKC FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9EA:7-(3-{[4-(4-ACETYLPIPERAZIN-1-YL)PHENOXY]METHYL}-1,5-DIMETHYL-1H-PYRAZOL-4-YL)-3-{3-[(NAPHTHALEN-1-YL)OXY]PROPYL}-1-[(PYRIDIN-3-YL)METHYL]-1H-INDOLE-2-CARBOXYLIC+ACID'>9EA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=5vkc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vkc OCA], [http://pdbe.org/5vkc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5vkc RCSB], [http://www.ebi.ac.uk/pdbsum/5vkc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5vkc ProSAT]</span></td></tr>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/MCL1_HUMAN MCL1_HUMAN]] Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis.<ref>PMID:10766760</ref>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Myeloid cell leukemia 1 (MCL-1) is a BCL-2 family protein that has been implicated in the progression and survival of multiple tumor types. Herein we report a series of MCL-1 inhibitors that emanated from a high throughput screening (HTS) hit and progressed via iterative cycles of structure-guided design. Advanced compounds from this series exhibited subnanomolar affinity for MCL-1 and excellent selectivity over other BCL-2 family proteins as well as multiple kinases and GPCRs. In a MCL-1 dependent human tumor cell line, administration of compound 30b rapidly induced caspase activation with associated loss in cell viability. The small molecules described herein thus comprise effective tools for studying MCL-1 biology.

Structure-guided design of a series of MCL-1 inhibitors with high affinity and selectivity.,Bruncko M, Wang L, Sheppard GS, Phillips DC, Tahir SK, Xue J, Erickson S, Fidanze S, Fry E, Hasvold L, Jenkins GJ, Jin S, Judge RA, Kovar PJ, Madar D, Nimmer P, Park C, Petros AM, Rosenberg SH, Smith ML, Song X, Sun C, Tao ZF, Wang X, Xiao Y, Zhang H, Tse C, Leverson JD, Elmore SW, Souers AJ J Med Chem. 2015 Mar 12;58(5):2180-94. doi: 10.1021/jm501258m. Epub 2015 Feb 26. PMID:25679114<ref>PMID:25679114</ref>

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5vkc" style="background-color:#fffaf0;"></div>
== References ==
<references/>
TOC
</StructureSection>
[[Category: Judge, R A]]
[[Category: Souers, A J]]
[[Category: Mcl-1]]
[[Category: Signaling protein-inhibitor complex]]