4bxn - Revision history

OCA at 07:47, 7 February 2024

2024-02-07T07:47:24Z

←Older revision		Revision as of 07:47, 7 February 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4bxn]] 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=4BXN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BXN FirstGlance]. <br>		<table><tr><td colspan='2'>[[4bxn]] 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=4BXN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BXN FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6LX:N-(3-AMINOPROPYL)-N-[(1R)-1-(3-BENZYL-7-CHLORO-4-OXO-4H-CHROMEN-2-YL)-2-METHYLPROPYL]-4-METHYLBENZAMIDE'>6LX</scene>, <scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=CD:CADMIUM+ION'>CD</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</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]] 2.793Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6LX:N-(3-AMINOPROPYL)-N-[(1R)-1-(3-BENZYL-7-CHLORO-4-OXO-4H-CHROMEN-2-YL)-2-METHYLPROPYL]-4-METHYLBENZAMIDE'>6LX</scene>, <scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=CD:CADMIUM+ION'>CD</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</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=4bxn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bxn OCA], [https://pdbe.org/4bxn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bxn RCSB], [https://www.ebi.ac.uk/pdbsum/4bxn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bxn 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=4bxn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bxn OCA], [https://pdbe.org/4bxn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bxn RCSB], [https://www.ebi.ac.uk/pdbsum/4bxn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bxn ProSAT]</span></td></tr>
	</table>		</table>
Line 11:		Line 12:
	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/KIF11_HUMAN KIF11_HUMAN] Motor protein required for establishing a bipolar spindle. Blocking of KIF11 prevents centrosome migration and arrest cells in mitosis with monoastral microtubule arrays.<ref>PMID:19001501</ref>		[https://www.uniprot.org/uniprot/KIF11_HUMAN KIF11_HUMAN] Motor protein required for establishing a bipolar spindle. Blocking of KIF11 prevents centrosome migration and arrest cells in mitosis with monoastral microtubule arrays.<ref>PMID:19001501</ref>
-	<div style="background-color:#fffaf0;">
-	== Publication Abstract from PubMed ==
-	Development of drug resistance during cancer chemotherapy is one of the major causes of chemotherapeutic failure for the majority of clinical agents. The aim of this study was to investigate the underlying molecular mechanism of resistance developed by the mitotic kinesin Eg5 against the potent second-generation ispinesib analogue SB743921 (1), a phase I/II clinical candidate. Biochemical and biophysical data demonstrate that point mutations in the inhibitor-binding pocket decrease the efficacy of 1 by several 1000-fold. Surprisingly, the structures of wild type and mutant Eg5 in complex with 1 display no apparent structural changes in the binding configuration of the drug candidate. Furthermore, ITC and modelling approaches reveal that resistance to 1 is not through conventional steric effects at the binding site, but through reduced flexibility and changes in energy fluctuation pathways through the protein that influence its function. This is a phenomenon we have called 'resistance by allostery'.
-
-	The Mitotic Kinesin Eg5 Overcomes Inhibition to the Phase I/II Clinical Candidate SB743921 by an Allosteric Resistance Mechanism.,Talapatra SK, Anthony NG, Mackay SP, Kozielski F J Med Chem. 2013 Jul 22. PMID:23875972<ref>PMID:23875972</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 4bxn" style="background-color:#fffaf0;"></div>

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

OCA at 07:39, 8 March 2023

2023-03-08T07:39:13Z

←Older revision		Revision as of 07:39, 8 March 2023
Line 8:		Line 8:
	</table>		</table>
	== Disease ==		== Disease ==
-	[[https://www.uniprot.org/uniprot/KIF11_HUMAN KIF11_HUMAN]] Defects in KIF11 are the cause of microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR) [MIM:[https://omim.org/entry/152950 152950]]. An autosomal dominant disorder that involves an overlapping but variable spectrum of central nervous system and ocular developmental anomalies. Microcephaly ranges from mild to severe and is often associated with mild to moderate developmental delay and a characteristic facial phenotype with upslanting palpebral fissures, broad nose with rounded tip, long philtrum with thin upper lip, prominent chin, and prominent ears. Chorioretinopathy is the most common eye abnormality, but retinal folds, microphthalmia, and myopic and hypermetropic astigmatism have also been reported, and some individuals have no overt ocular phenotype. Congenital lymphedema, when present, is typically confined to the dorsa of the feet, and lymphoscintigraphy reveals the absence of radioactive isotope uptake from the webspaces between the toes.<ref>PMID:22284827</ref>	+	[https://www.uniprot.org/uniprot/KIF11_HUMAN KIF11_HUMAN] Defects in KIF11 are the cause of microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR) [MIM:[https://omim.org/entry/152950 152950]. An autosomal dominant disorder that involves an overlapping but variable spectrum of central nervous system and ocular developmental anomalies. Microcephaly ranges from mild to severe and is often associated with mild to moderate developmental delay and a characteristic facial phenotype with upslanting palpebral fissures, broad nose with rounded tip, long philtrum with thin upper lip, prominent chin, and prominent ears. Chorioretinopathy is the most common eye abnormality, but retinal folds, microphthalmia, and myopic and hypermetropic astigmatism have also been reported, and some individuals have no overt ocular phenotype. Congenital lymphedema, when present, is typically confined to the dorsa of the feet, and lymphoscintigraphy reveals the absence of radioactive isotope uptake from the webspaces between the toes.<ref>PMID:22284827</ref>
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/KIF11_HUMAN KIF11_HUMAN]] Motor protein required for establishing a bipolar spindle. Blocking of KIF11 prevents centrosome migration and arrest cells in mitosis with monoastral microtubule arrays.<ref>PMID:19001501</ref>	+	[https://www.uniprot.org/uniprot/KIF11_HUMAN KIF11_HUMAN] Motor protein required for establishing a bipolar spindle. Blocking of KIF11 prevents centrosome migration and arrest cells in mitosis with monoastral microtubule arrays.<ref>PMID:19001501</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Development of drug resistance during cancer chemotherapy is one of the major causes of chemotherapeutic failure for the majority of clinical agents. The aim of this study was to investigate the underlying molecular mechanism of resistance developed by the mitotic kinesin Eg5 against the potent second-generation ispinesib analogue SB743921 (1), a phase I/II clinical candidate. Biochemical and biophysical data demonstrate that point mutations in the inhibitor-binding pocket decrease the efficacy of 1 by several 1000-fold. Surprisingly, the structures of wild type and mutant Eg5 in complex with 1 display no apparent structural changes in the binding configuration of the drug candidate. Furthermore, ITC and modelling approaches reveal that resistance to 1 is not through conventional steric effects at the binding site, but through reduced flexibility and changes in energy fluctuation pathways through the protein that influence its function. This is a phenomenon we have called 'resistance by allostery'.
		+
		+	The Mitotic Kinesin Eg5 Overcomes Inhibition to the Phase I/II Clinical Candidate SB743921 by an Allosteric Resistance Mechanism.,Talapatra SK, Anthony NG, Mackay SP, Kozielski F J Med Chem. 2013 Jul 22. PMID:23875972<ref>PMID:23875972</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 4bxn" style="background-color:#fffaf0;"></div>

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

OCA at 17:15, 7 September 2022

2022-09-07T17:15:16Z

←Older revision		Revision as of 17:15, 7 September 2022
Line 3:		Line 3:
	<StructureSection load='4bxn' size='340' side='right'caption='[[4bxn]], [[Resolution\|resolution]] 2.79Å' scene=''>		<StructureSection load='4bxn' size='340' side='right'caption='[[4bxn]], [[Resolution\|resolution]] 2.79Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4bxn]] 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=4BXN OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4BXN FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4bxn]] 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=4BXN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BXN FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6LX:N-(3-AMINOPROPYL)-N-[(1R)-1-(3-BENZYL-7-CHLORO-4-OXO-4H-CHROMEN-2-YL)-2-METHYLPROPYL]-4-METHYLBENZAMIDE'>6LX</scene>, <scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=CD:CADMIUM+ION'>CD</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6LX:N-(3-AMINOPROPYL)-N-[(1R)-1-(3-BENZYL-7-CHLORO-4-OXO-4H-CHROMEN-2-YL)-2-METHYLPROPYL]-4-METHYLBENZAMIDE'>6LX</scene>, <scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=CD:CADMIUM+ION'>CD</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</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=4bxn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bxn OCA], [~~http~~://pdbe.org/4bxn PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4bxn RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4bxn PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4bxn 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=4bxn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bxn OCA], [https://pdbe.org/4bxn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bxn RCSB], [https://www.ebi.ac.uk/pdbsum/4bxn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bxn ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[[~~http~~://www.uniprot.org/uniprot/KIF11_HUMAN KIF11_HUMAN]] Defects in KIF11 are the cause of microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR) [MIM:[~~http~~://omim.org/entry/152950 152950]]. An autosomal dominant disorder that involves an overlapping but variable spectrum of central nervous system and ocular developmental anomalies. Microcephaly ranges from mild to severe and is often associated with mild to moderate developmental delay and a characteristic facial phenotype with upslanting palpebral fissures, broad nose with rounded tip, long philtrum with thin upper lip, prominent chin, and prominent ears. Chorioretinopathy is the most common eye abnormality, but retinal folds, microphthalmia, and myopic and hypermetropic astigmatism have also been reported, and some individuals have no overt ocular phenotype. Congenital lymphedema, when present, is typically confined to the dorsa of the feet, and lymphoscintigraphy reveals the absence of radioactive isotope uptake from the webspaces between the toes.<ref>PMID:22284827</ref>	+	[[https://www.uniprot.org/uniprot/KIF11_HUMAN KIF11_HUMAN]] Defects in KIF11 are the cause of microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR) [MIM:[https://omim.org/entry/152950 152950]]. An autosomal dominant disorder that involves an overlapping but variable spectrum of central nervous system and ocular developmental anomalies. Microcephaly ranges from mild to severe and is often associated with mild to moderate developmental delay and a characteristic facial phenotype with upslanting palpebral fissures, broad nose with rounded tip, long philtrum with thin upper lip, prominent chin, and prominent ears. Chorioretinopathy is the most common eye abnormality, but retinal folds, microphthalmia, and myopic and hypermetropic astigmatism have also been reported, and some individuals have no overt ocular phenotype. Congenital lymphedema, when present, is typically confined to the dorsa of the feet, and lymphoscintigraphy reveals the absence of radioactive isotope uptake from the webspaces between the toes.<ref>PMID:22284827</ref>
	== Function ==		== Function ==
-	[[~~http~~://www.uniprot.org/uniprot/KIF11_HUMAN KIF11_HUMAN]] Motor protein required for establishing a bipolar spindle. Blocking of KIF11 prevents centrosome migration and arrest cells in mitosis with monoastral microtubule arrays.<ref>PMID:19001501</ref>	+	[[https://www.uniprot.org/uniprot/KIF11_HUMAN KIF11_HUMAN]] Motor protein required for establishing a bipolar spindle. Blocking of KIF11 prevents centrosome migration and arrest cells in mitosis with monoastral microtubule arrays.<ref>PMID:19001501</ref>
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	Development of drug resistance during cancer chemotherapy is one of the major causes of chemotherapeutic failure for the majority of clinical agents. The aim of this study was to investigate the underlying molecular mechanism of resistance developed by the mitotic kinesin Eg5 against the potent second-generation ispinesib analogue SB743921 (1), a phase I/II clinical candidate. Biochemical and biophysical data demonstrate that point mutations in the inhibitor-binding pocket decrease the efficacy of 1 by several 1000-fold. Surprisingly, the structures of wild type and mutant Eg5 in complex with 1 display no apparent structural changes in the binding configuration of the drug candidate. Furthermore, ITC and modelling approaches reveal that resistance to 1 is not through conventional steric effects at the binding site, but through reduced flexibility and changes in energy fluctuation pathways through the protein that influence its function. This is a phenomenon we have called 'resistance by allostery'.	+
-		+
-	The Mitotic Kinesin Eg5 Overcomes Inhibition to the Phase I/II Clinical Candidate SB743921 by an Allosteric Resistance Mechanism.,Talapatra SK, Anthony NG, Mackay SP, Kozielski F J Med Chem. 2013 Jul 22. PMID:23875972<ref>PMID:23875972</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 4bxn" style="background-color:#fffaf0;"></div~~>	+

	==See Also==		==See Also==
Line 27:		Line 18:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Anthony~~, N G~~]]	+	[[Category: Anthony NG]]
-	[[Category: Kozielski, F]]	+	[[Category: Kozielski F]]
-	[[Category: Mackay~~, S P~~]]	+	[[Category: Mackay SP]]
-	[[Category: Talapatra~~, S K]]~~	+	[[Category: Talapatra SK]]
-	~~[[Category: Mitosis]]~~	+
-	~~[[Category: Motor protein~~]]	+

OCA at 15:56, 20 November 2019

2019-11-20T15:56:08Z

←Older revision		Revision as of 15:56, 20 November 2019
Line 22:		Line 22:

	==See Also==		==See Also==
-	*[[Kinesin\|Kinesin]]	+	*[[Kinesin 3D Structures\|Kinesin 3D Structures]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 13:49, 13 March 2019

2019-03-13T13:49:01Z

←Older revision		Revision as of 13:49, 13 March 2019
Line 1:		Line 1:

	==Eg5(WT) complex==		==Eg5(WT) complex==
-	<StructureSection load='4bxn' size='340' side='right' caption='[[4bxn]], [[Resolution\|resolution]] 2.79Å' scene=''>	+	<StructureSection load='4bxn' size='340' side='right'caption='[[4bxn]], [[Resolution\|resolution]] 2.79Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4bxn]] 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=4BXN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BXN FirstGlance]. <br>		<table><tr><td colspan='2'>[[4bxn]] 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=4BXN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BXN FirstGlance]. <br>
Line 28:		Line 28:
	</StructureSection>		</StructureSection>
	[[Category: Human]]		[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Anthony, N G]]		[[Category: Anthony, N G]]
	[[Category: Kozielski, F]]		[[Category: Kozielski, F]]

OCA at 07:23, 23 December 2016

2016-12-23T07:23:43Z

←Older revision		Revision as of 07:23, 23 December 2016
Line 1:		Line 1:
		+
	==Eg5(WT) complex==		==Eg5(WT) complex==
	<StructureSection load='4bxn' size='340' side='right' caption='[[4bxn]], [[Resolution\|resolution]] 2.79Å' scene=''>		<StructureSection load='4bxn' size='340' side='right' caption='[[4bxn]], [[Resolution\|resolution]] 2.79Å' scene=''>
Line 4:		Line 5:
	<table><tr><td colspan='2'>[[4bxn]] 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=4BXN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BXN FirstGlance]. <br>		<table><tr><td colspan='2'>[[4bxn]] 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=4BXN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BXN FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6LX:N-(3-AMINOPROPYL)-N-[(1R)-1-(3-BENZYL-7-CHLORO-4-OXO-4H-CHROMEN-2-YL)-2-METHYLPROPYL]-4-METHYLBENZAMIDE'>6LX</scene>, <scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=CD:CADMIUM+ION'>CD</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6LX:N-(3-AMINOPROPYL)-N-[(1R)-1-(3-BENZYL-7-CHLORO-4-OXO-4H-CHROMEN-2-YL)-2-METHYLPROPYL]-4-METHYLBENZAMIDE'>6LX</scene>, <scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=CD:CADMIUM+ION'>CD</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</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=4bxn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bxn OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4bxn RCSB], [http://www.ebi.ac.uk/pdbsum/4bxn 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=4bxn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bxn OCA], [http://pdbe.org/4bxn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4bxn RCSB], [http://www.ebi.ac.uk/pdbsum/4bxn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4bxn ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 18:		Line 19:
	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 4bxn" style="background-color:#fffaf0;"></div>

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

OCA at 10:48, 20 January 2015

2015-01-20T10:48:33Z

←Older revision		Revision as of 10:48, 20 January 2015
Line 3:		Line 3:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4bxn]] 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=4BXN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BXN FirstGlance]. <br>		<table><tr><td colspan='2'>[[4bxn]] 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=4BXN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BXN FirstGlance]. <br>
-	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6LX:N-(3-AMINOPROPYL)-N-[(1R)-1-(3-BENZYL-7-CHLORO-4-OXO-4H-CHROMEN-2-YL)-2-METHYLPROPYL]-4-METHYLBENZAMIDE'>6LX</scene>, <scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=CD:CADMIUM+ION'>CD</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene><br>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6LX:N-(3-AMINOPROPYL)-N-[(1R)-1-(3-BENZYL-7-CHLORO-4-OXO-4H-CHROMEN-2-YL)-2-METHYLPROPYL]-4-METHYLBENZAMIDE'>6LX</scene>, <scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=CD:CADMIUM+ION'>CD</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr>
-	<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4bxn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bxn OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4bxn RCSB], [http://www.ebi.ac.uk/pdbsum/4bxn 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=4bxn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bxn OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4bxn RCSB], [http://www.ebi.ac.uk/pdbsum/4bxn PDBsum]</span></td></tr>
-	<table>	+	</table>
	== Disease ==		== Disease ==
	[[http://www.uniprot.org/uniprot/KIF11_HUMAN KIF11_HUMAN]] Defects in KIF11 are the cause of microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR) [MIM:[http://omim.org/entry/152950 152950]]. An autosomal dominant disorder that involves an overlapping but variable spectrum of central nervous system and ocular developmental anomalies. Microcephaly ranges from mild to severe and is often associated with mild to moderate developmental delay and a characteristic facial phenotype with upslanting palpebral fissures, broad nose with rounded tip, long philtrum with thin upper lip, prominent chin, and prominent ears. Chorioretinopathy is the most common eye abnormality, but retinal folds, microphthalmia, and myopic and hypermetropic astigmatism have also been reported, and some individuals have no overt ocular phenotype. Congenital lymphedema, when present, is typically confined to the dorsa of the feet, and lymphoscintigraphy reveals the absence of radioactive isotope uptake from the webspaces between the toes.<ref>PMID:22284827</ref>		[[http://www.uniprot.org/uniprot/KIF11_HUMAN KIF11_HUMAN]] Defects in KIF11 are the cause of microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR) [MIM:[http://omim.org/entry/152950 152950]]. An autosomal dominant disorder that involves an overlapping but variable spectrum of central nervous system and ocular developmental anomalies. Microcephaly ranges from mild to severe and is often associated with mild to moderate developmental delay and a characteristic facial phenotype with upslanting palpebral fissures, broad nose with rounded tip, long philtrum with thin upper lip, prominent chin, and prominent ears. Chorioretinopathy is the most common eye abnormality, but retinal folds, microphthalmia, and myopic and hypermetropic astigmatism have also been reported, and some individuals have no overt ocular phenotype. Congenital lymphedema, when present, is typically confined to the dorsa of the feet, and lymphoscintigraphy reveals the absence of radioactive isotope uptake from the webspaces between the toes.<ref>PMID:22284827</ref>
Line 26:		Line 26:
	</StructureSection>		</StructureSection>
	[[Category: Human]]		[[Category: Human]]
-	[[Category: Anthony, N G.]]	+	[[Category: Anthony, N G]]
-	[[Category: Kozielski, F.]]	+	[[Category: Kozielski, F]]
-	[[Category: Mackay, S P.]]	+	[[Category: Mackay, S P]]
-	[[Category: Talapatra, S K.]]	+	[[Category: Talapatra, S K]]
	[[Category: Mitosis]]		[[Category: Mitosis]]
	[[Category: Motor protein]]		[[Category: Motor protein]]

OCA at 07:00, 24 September 2014

2014-09-24T07:00:38Z

←Older revision		Revision as of 07:00, 24 September 2014
Line 1:		Line 1:
-	~~{{STRUCTURE_4bxn\| PDB~~=4bxn \| ~~SCENE~~= }}	+	==Eg5(WT) complex==
-	===~~Eg5~~(WT) ~~complex~~===	+	<StructureSection load='4bxn' size='340' side='right' caption='[[4bxn]], [[Resolution\|resolution]] 2.79Å' scene=''>
-	~~{{ABSTRACT_PUBMED_23875972}}~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[4bxn]] 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=4BXN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BXN FirstGlance]. <br>
-	==Disease==	+	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6LX:N-(3-AMINOPROPYL)-N-[(1R)-1-(3-BENZYL-7-CHLORO-4-OXO-4H-CHROMEN-2-YL)-2-METHYLPROPYL]-4-METHYLBENZAMIDE'>6LX</scene>, <scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=CD:CADMIUM+ION'>CD</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene><br>
		+	<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4bxn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bxn OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4bxn RCSB], [http://www.ebi.ac.uk/pdbsum/4bxn PDBsum]</span></td></tr>
		+	<table>
		+	== Disease ==
	[[http://www.uniprot.org/uniprot/KIF11_HUMAN KIF11_HUMAN]] Defects in KIF11 are the cause of microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR) [MIM:[http://omim.org/entry/152950 152950]]. An autosomal dominant disorder that involves an overlapping but variable spectrum of central nervous system and ocular developmental anomalies. Microcephaly ranges from mild to severe and is often associated with mild to moderate developmental delay and a characteristic facial phenotype with upslanting palpebral fissures, broad nose with rounded tip, long philtrum with thin upper lip, prominent chin, and prominent ears. Chorioretinopathy is the most common eye abnormality, but retinal folds, microphthalmia, and myopic and hypermetropic astigmatism have also been reported, and some individuals have no overt ocular phenotype. Congenital lymphedema, when present, is typically confined to the dorsa of the feet, and lymphoscintigraphy reveals the absence of radioactive isotope uptake from the webspaces between the toes.<ref>PMID:22284827</ref>		[[http://www.uniprot.org/uniprot/KIF11_HUMAN KIF11_HUMAN]] Defects in KIF11 are the cause of microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR) [MIM:[http://omim.org/entry/152950 152950]]. An autosomal dominant disorder that involves an overlapping but variable spectrum of central nervous system and ocular developmental anomalies. Microcephaly ranges from mild to severe and is often associated with mild to moderate developmental delay and a characteristic facial phenotype with upslanting palpebral fissures, broad nose with rounded tip, long philtrum with thin upper lip, prominent chin, and prominent ears. Chorioretinopathy is the most common eye abnormality, but retinal folds, microphthalmia, and myopic and hypermetropic astigmatism have also been reported, and some individuals have no overt ocular phenotype. Congenital lymphedema, when present, is typically confined to the dorsa of the feet, and lymphoscintigraphy reveals the absence of radioactive isotope uptake from the webspaces between the toes.<ref>PMID:22284827</ref>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/KIF11_HUMAN KIF11_HUMAN]] Motor protein required for establishing a bipolar spindle. Blocking of KIF11 prevents centrosome migration and arrest cells in mitosis with monoastral microtubule arrays.<ref>PMID:19001501</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Development of drug resistance during cancer chemotherapy is one of the major causes of chemotherapeutic failure for the majority of clinical agents. The aim of this study was to investigate the underlying molecular mechanism of resistance developed by the mitotic kinesin Eg5 against the potent second-generation ispinesib analogue SB743921 (1), a phase I/II clinical candidate. Biochemical and biophysical data demonstrate that point mutations in the inhibitor-binding pocket decrease the efficacy of 1 by several 1000-fold. Surprisingly, the structures of wild type and mutant Eg5 in complex with 1 display no apparent structural changes in the binding configuration of the drug candidate. Furthermore, ITC and modelling approaches reveal that resistance to 1 is not through conventional steric effects at the binding site, but through reduced flexibility and changes in energy fluctuation pathways through the protein that influence its function. This is a phenomenon we have called 'resistance by allostery'.

-	~~==Function==~~	+	The Mitotic Kinesin Eg5 Overcomes Inhibition to the Phase I/II Clinical Candidate SB743921 by an Allosteric Resistance Mechanism.,Talapatra SK, Anthony NG, Mackay SP, Kozielski F J Med Chem. 2013 Jul 22. PMID:23875972<ref>PMID:23875972</ref>
-	~~[[http:~~/~~/www~~.~~uniprot~~.org/uniprot/KIF11_HUMAN KIF11_HUMAN]] Motor protein required for establishing a bipolar spindle. Blocking of KIF11 prevents centrosome migration and arrest cells in mitosis with monoastral microtubule arrays.<ref>PMID:~~19001501~~</ref>	+

-	~~==About this Structure==~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[4bxn]] is~~ a ~~2 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=4BXN OCA].~~	+	</div>

-	==~~Reference~~==	+	==See Also==
-	~~<ref group~~=~~"xtra">PMID:023875972</ref>~~<references ~~group="xtra"~~/><~~references~~/>	+	*[[Kinesin\|Kinesin]]
-	[[Category: ~~Homo sapiens~~]]	+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Human]]
	[[Category: Anthony, N G.]]		[[Category: Anthony, N G.]]
	[[Category: Kozielski, F.]]		[[Category: Kozielski, F.]]

OCA at 05:14, 1 August 2013

2013-08-01T05:14:14Z

←Older revision		Revision as of 05:14, 1 August 2013
Line 1:		Line 1:
-	~~'''Unreleased structure'''~~	+	{{STRUCTURE_4bxn\| PDB=4bxn \| SCENE= }}
		+	===Eg5(WT) complex===
		+	{{ABSTRACT_PUBMED_23875972}}

-	~~The~~ entry ~~4bxn~~ is ~~ON HOLD~~ ~~until Paper Publication~~	+	==Disease==
		+	[[http://www.uniprot.org/uniprot/KIF11_HUMAN KIF11_HUMAN]] Defects in KIF11 are the cause of microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR) [MIM:[http://omim.org/entry/152950 152950]]. An autosomal dominant disorder that involves an overlapping but variable spectrum of central nervous system and ocular developmental anomalies. Microcephaly ranges from mild to severe and is often associated with mild to moderate developmental delay and a characteristic facial phenotype with upslanting palpebral fissures, broad nose with rounded tip, long philtrum with thin upper lip, prominent chin, and prominent ears. Chorioretinopathy is the most common eye abnormality, but retinal folds, microphthalmia, and myopic and hypermetropic astigmatism have also been reported, and some individuals have no overt ocular phenotype. Congenital lymphedema, when present, is typically confined to the dorsa of the feet, and lymphoscintigraphy reveals the absence of radioactive isotope uptake from the webspaces between the toes.<ref>PMID:22284827</ref>

-	~~Authors~~: ~~Talapatra, S~~.K.~~, Anthony, N~~.~~G., Mackay, S.P., Kozielski, F~~.	+	==Function==
		+	[[http://www.uniprot.org/uniprot/KIF11_HUMAN KIF11_HUMAN]] Motor protein required for establishing a bipolar spindle. Blocking of KIF11 prevents centrosome migration and arrest cells in mitosis with monoastral microtubule arrays.<ref>PMID:19001501</ref>

-	~~Description~~: ~~Eg5(WT) complex~~	+	==About this Structure==
		+	[[4bxn]] is a 2 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=4BXN OCA].
		+
		+	==Reference==
		+	<ref group="xtra">PMID:023875972</ref><references group="xtra"/><references/>
		+	[[Category: Homo sapiens]]
		+	[[Category: Anthony, N G.]]
		+	[[Category: Kozielski, F.]]
		+	[[Category: Mackay, S P.]]
		+	[[Category: Talapatra, S K.]]
		+	[[Category: Mitosis]]
		+	[[Category: Motor protein]]

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

2013-07-24T12:03:05Z

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

←Older revision

Revision as of 12:03, 24 July 2013