6g32 - Revision history

OCA at 06:58, 24 October 2018

OCA — Wed, 24 Oct 2018 06:58:49 GMT

←Older revision		Revision as of 06:58, 24 October 2018
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	<StructureSection load='6g32' size='340' side='right' caption='[[6g32]], [[Resolution\|resolution]] 3.28Å' scene=''>		<StructureSection load='6g32' size='340' side='right' caption='[[6g32]], [[Resolution\|resolution]] 3.28Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6g32]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6G32 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6G32 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6g32]] is a 6 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=6G32 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6G32 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">GGPS1 ([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=6g32 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6g32 OCA], [http://pdbe.org/6g32 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6g32 RCSB], [http://www.ebi.ac.uk/pdbsum/6g32 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6g32 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=6g32 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6g32 OCA], [http://pdbe.org/6g32 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6g32 RCSB], [http://www.ebi.ac.uk/pdbsum/6g32 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6g32 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
	[[http://www.uniprot.org/uniprot/GGPPS_HUMAN GGPPS_HUMAN]] Catalyzes the trans-addition of the three molecules of IPP onto DMAPP to form geranylgeranyl pyrophosphate, an important precursor of carotenoids and geranylated proteins.		[[http://www.uniprot.org/uniprot/GGPPS_HUMAN GGPPS_HUMAN]] Catalyzes the trans-addition of the three molecules of IPP onto DMAPP to form geranylgeranyl pyrophosphate, an important precursor of carotenoids and geranylated proteins.
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Bisphosphonates are widely used for treating osteoporosis, a common disorder in which bone strength is reduced, increasing the risk for fractures. Rarely, bisphosphonates can paradoxically lead to atypical fractures occurring spontaneously or with trivial trauma. Recently, a novel missense mutation (D188Y) in the GGPS1 gene, encoding for geranylgeranyl diphosphate synthase (GGPPS), was associated with bisphosphonates- induced atypical fractures. However, the molecular basis for GGPPS involvement in this devastating condition remains elusive. Here, we show that while maintaining an overall unperturbed global enzyme structure, the D188Y mutation leads to a ~4-fold catalytic activity decrease. Furthermore, GGPPS-D188Y is unable to support cross-species complementation, highlighting the functional significance of the reduced catalytic activity observed in vitro. We next determined the crystal structure of apo GGPPS-D188Y, revealing that while Y188 does not alter the protein fold, its bulky side-chain sterically interferes with substrate binding. In agreement, we show that GGPPS-D188Y exhibits ~3-fold reduction in the binding affinity of zoledronate, a commonly used bisphosphonate. However, inhibition of the mutated enzyme by zoledronate, in pharmacologically-relevant concentrations, is maintained. Finally, we determined the crystal structure of zoledronate-bound GGPPS-D188Y, revealing large ligand- induced binding pocket rearrangements, revising the previous model for GGPPS- bisphosphonates interaction. In conclusion, we propose that among heterozygotes residual GGPPS activity is sufficient to support physiological cellular function, concealing any pathologic phenotype. However, under bisphosphonates treatment, GGPPS activity is reduced below a crucial threshold for osteoclasts function, leading to impaired bone remodeling and increased susceptibility to atypical fractures.
		+
		+	Reduced Activity of GGPPS Mutant is Involved in Bisphosphonates-Induced Atypical Fractures.,Lisnyansky M, Kapelushnik N, Ben-Bassat A, Marom M, Loewenstein A, Khananshvili D, Giladi M, Haitin Y Mol Pharmacol. 2018 Oct 1. pii: mol.118.113670. doi: 10.1124/mol.118.113670. PMID:30275041<ref>PMID:30275041</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 6g32" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Ben-Bassat, A]]		[[Category: Ben-Bassat, A]]
	[[Category: Giladi, M]]		[[Category: Giladi, M]]

OCA at 08:05, 17 October 2018

OCA — Wed, 17 Oct 2018 08:05:49 GMT

←Older revision		Revision as of 08:05, 17 October 2018
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-	'''Unreleased structure'''

-	~~The entry~~ 6g32 is ~~ON HOLD until Paper Publication~~	+	==Crystal structure of human geranylgeranyl diphosphate synthase mutant D188Y==
-		+	<StructureSection load='6g32' size='340' side='right' caption='[[6g32]], [[Resolution\|resolution]] 3.28Å' scene=''>
-	~~Authors~~:	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[6g32]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6G32 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6G32 FirstGlance]. <br>
-	~~Description~~:	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
-	[[Category: ~~Unreleased Structures~~]]	+	<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=6g32 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6g32 OCA], [http://pdbe.org/6g32 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6g32 RCSB], [http://www.ebi.ac.uk/pdbsum/6g32 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6g32 ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/GGPPS_HUMAN GGPPS_HUMAN]] Catalyzes the trans-addition of the three molecules of IPP onto DMAPP to form geranylgeranyl pyrophosphate, an important precursor of carotenoids and geranylated proteins.
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Ben-Bassat, A]]
		+	[[Category: Giladi, M]]
		+	[[Category: Haitin, Y]]
		+	[[Category: Kapelushnik, N]]
		+	[[Category: Khananshvili, D]]
		+	[[Category: Lisnyansky, M]]
		+	[[Category: Loewenstein, A]]
		+	[[Category: Marom, M]]
		+	[[Category: Geranylgeranyl diphosphate synthase]]
		+	[[Category: Ggpp]]
		+	[[Category: Mevalonate pathway]]
		+	[[Category: Prenyltransferase]]
		+	[[Category: Transferase]]

OCA at 06:50, 2 May 2018

OCA — Wed, 02 May 2018 06:50:59 GMT

←Older revision		Revision as of 06:50, 2 May 2018
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6g32 is ON HOLD	+	The entry 6g32 is ON HOLD until Paper Publication

	Authors:		Authors:

OCA: Protected "6g32" [edit=sysop:move=sysop]

OCA — Wed, 04 Apr 2018 04:49:09 GMT

Protected "6g32" [edit=sysop:move=sysop]

←Older revision

Revision as of 04:49, 4 April 2018

OCA: New page: '''Unreleased structure''' The entry 6g32 is ON HOLD Authors: Description: Category: Unreleased Structures

OCA — Wed, 04 Apr 2018 04:49:07 GMT

New page: '''Unreleased structure''' The entry 6g32 is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 6g32 is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]