View source for 6ccx


==NMR data-driven model of GTPase KRas-GMPPNP:Cmpd2 complex tethered to a nanodisc==
<StructureSection load='6ccx' size='340' side='right'caption='[[6ccx]]' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6ccx]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CCX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6CCX FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=17F:O-[(S)-({(2R)-2,3-BIS[(9Z)-OCTADEC-9-ENOYLOXY]PROPYL}OXY)(HYDROXY)PHOSPHORYL]-L-SERINE'>17F</scene>, <scene name='pdbligand=EWS:(2R,4S)-4-[(5-bromo-1H-indole-3-carbonyl)amino]-2-[(4-chlorophenyl)methyl]piperidin-1-ium'>EWS</scene>, <scene name='pdbligand=GNP:PHOSPHOAMINOPHOSPHONIC+ACID-GUANYLATE+ESTER'>GNP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PCW:1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE'>PCW</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=6ccx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ccx OCA], [https://pdbe.org/6ccx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ccx RCSB], [https://www.ebi.ac.uk/pdbsum/6ccx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ccx ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/APOA1_HUMAN APOA1_HUMAN] Defects in APOA1 are a cause of high density lipoprotein deficiency type 2 (HDLD2) [MIM:[https://omim.org/entry/604091 604091]; also known as familial hypoalphalipoproteinemia (FHA). Inheritance is autosomal dominant.<ref>PMID:8240372</ref> <ref>PMID:8282791</ref>   Defects in APOA1 are a cause of the low HDL levels observed in high density lipoprotein deficiency type 1 (HDLD1) [MIM:[https://omim.org/entry/205400 205400]; also known as analphalipoproteinemia or Tangier disease (TGD). HDLD1 is a recessive disorder characterized by the absence of plasma HDL, accumulation of cholesteryl esters, premature coronary artery disease, hepatosplenomegaly, recurrent peripheral neuropathy and progressive muscle wasting and weakness. In HDLD1 patients, ApoA-I fails to associate with HDL probably because of the faulty conversion of pro-ApoA-I molecules into mature chains, either due to a defect in the converting enzyme activity or a specific structural defect in Tangier ApoA-I.<ref>PMID:8240372</ref> <ref>PMID:8282791</ref>   Note=A mutation in APOA1 is the cause of amyloid polyneuropathy-nephropathy Iowa type (AMYLIOWA); also known as amyloidosis van Allen type or familial amyloid polyneuropathy type III. AMYLIOWA is a hereditary generalized amyloidosis due to deposition of amyloid mainly constituted by apolipoprotein A1. The clinical picture is dominated by neuropathy in the early stages of the disease and nephropathy late in the course. Death is due in most cases to renal amyloidosis. Severe peptic ulcer disease can occurr in some and hearing loss is frequent. Cataracts is present in several, but vitreous opacities are not observed.<ref>PMID:8240372</ref> <ref>PMID:8282791</ref> <ref>PMID:3142462</ref> <ref>PMID:2123470</ref>   Defects in APOA1 are a cause of amyloidosis type 8 (AMYL8) [MIM:[https://omim.org/entry/105200 105200]; also known as systemic non-neuropathic amyloidosis or Ostertag-type amyloidosis. AMYL8 is a hereditary generalized amyloidosis due to deposition of apolipoprotein A1, fibrinogen and lysozyme amyloids. Viscera are particularly affected. There is no involvement of the nervous system. Clinical features include renal amyloidosis resulting in nephrotic syndrome, arterial hypertension, hepatosplenomegaly, cholestasis, petechial skin rash.<ref>PMID:8240372</ref> <ref>PMID:8282791</ref> <ref>PMID:1502149</ref> 
== Function ==
[https://www.uniprot.org/uniprot/APOA1_HUMAN APOA1_HUMAN] Participates in the reverse transport of cholesterol from tissues to the liver for excretion by promoting cholesterol efflux from tissues and by acting as a cofactor for the lecithin cholesterol acyltransferase (LCAT). As part of the SPAP complex, activates spermatozoa motility.<ref>PMID:1909888</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
KRAS is frequently mutated in several of the most lethal types of cancer; however, the KRAS protein has proven a challenging drug target. K-RAS4B must be localized to the plasma membrane by prenylation to activate oncogenic signaling, thus we endeavored to target the protein-membrane interface with small-molecule compounds. While all reported lead compounds have low affinity for KRAS in solution, the potency of Cmpd2 was strongly enhanced when prenylated K-RAS4B is associated with a lipid bilayer. We have elucidated a unique mechanism of action of Cmpd2, which simultaneously engages a shallow pocket on KRAS and associates with the lipid bilayer, thereby stabilizing KRAS in an orientation in which the membrane occludes its effector-binding site, reducing RAF binding and impairing activation of RAF. Furthermore, enrichment of Cmpd2 on the bilayer enhances potency by promoting interaction with KRAS. This insight reveals a novel approach to developing inhibitors of membrane-associated proteins.

Inhibition of K-RAS4B by a Unique Mechanism of Action: Stabilizing Membrane-Dependent Occlusion of the Effector-Binding Site.,Fang Z, Marshall CB, Nishikawa T, Gossert AD, Jansen JM, Jahnke W, Ikura M Cell Chem Biol. 2018 Aug 14. pii: S2451-9456(18)30261-7. doi:, 10.1016/j.chembiol.2018.07.009. PMID:30122370<ref>PMID:30122370</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6ccx" style="background-color:#fffaf0;"></div>

==See Also==
*[[GTPase KRas 3D structures|GTPase KRas 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Fang Z]]
[[Category: Gossert AD]]
[[Category: Ikura M]]
[[Category: Jahnke W]]
[[Category: Jansen JM]]
[[Category: Marshall CB]]
[[Category: Nishikawa T]]