PCSK9: Difference between revisions
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== Relevance == | == Relevance == | ||
Low levels of LDL receptor are a cause of hypercholesterolemia since LDLR removes LDL cholesterol from the blood. Thus PCSK9 is an important drug target as its level affects the amount of cholesterol in blood<ref>PMID:23317404</ref>. | Low levels of LDL receptor are a cause of hypercholesterolemia since LDLR removes LDL cholesterol from the blood. Thus PCSK9 is an important drug target as its level affects the amount of cholesterol in blood<ref>PMID:23317404</ref>. Inhibition of PCSK9 results in increased pathogen lipid clearance, decreased inflammatory response and improved septic shock outcome<ref>PMID:25320235</ref>. | ||
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==3D structures of PCSK9== | ==3D structures of PCSK9== | ||
Revision as of 09:56, 15 June 2016
<StructureSection load='2w2m' size='350' side='right' caption='Structure of human PCSK9 catalytic domain (grey) and prodomain (green) complex with LDL receptor EGF-A domain (magenta) and Ca+2 ion (PDB entry 2w2m)' scene=>
Function
PCSK9 or Proprotein Convertase Subtilisin/Kexin type 9 is a proteinase which is part of cholesterol synthesis[1]. PCSK9 undergoes autocatalysis producing an active enzyme from its precursor. PCSK9 binds to EGF-A domain of the LDL receptor (LDLR) inducing its degradation.
Relevance
Low levels of LDL receptor are a cause of hypercholesterolemia since LDLR removes LDL cholesterol from the blood. Thus PCSK9 is an important drug target as its level affects the amount of cholesterol in blood[2]. Inhibition of PCSK9 results in increased pathogen lipid clearance, decreased inflammatory response and improved septic shock outcome[3].
3D structures of PCSK9
Updated on 15-June-2016
2p4e, 2pmw, 2qtw – hPCSK9 – human
3bps, 2w2m, 3gcx – hPCSK9 + LDLR EGF-A
2w2n, 3gcw – hPCSK9 + LDLR EGF-A (mutant)
2w2o, 2w2p, 2w2q – hPCSK9 (mutant) + LDLR EGF-A
3h42 – hPCSK9 (mutant) + antibody
2xtj, 3sqo, 4k8r – hPCSK9 + antibody
3m0c – hPCSK9 (mutant) + LDLR
3p5b, 3p5c – hPCSK9 + LDLR variant
References
- ↑ Piper DE, Jackson S, Liu Q, Romanow WG, Shetterly S, Thibault ST, Shan B, Walker NP. The crystal structure of PCSK9: a regulator of plasma LDL-cholesterol. Structure. 2007 May;15(5):545-52. PMID:17502100 doi:https://dx.doi.org/10.1016/j.str.2007.04.004
- ↑ Seidah NG. Proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors in the treatment of hypercholesterolemia and other pathologies. Curr Pharm Des. 2013;19(17):3161-72. PMID:23317404
- ↑ Walley KR, Thain KR, Russell JA, Reilly MP, Meyer NJ, Ferguson JF, Christie JD, Nakada TA, Fjell CD, Thair SA, Cirstea MS, Boyd JH. PCSK9 is a critical regulator of the innate immune response and septic shock outcome. Sci Transl Med. 2014 Oct 15;6(258):258ra143. doi: 10.1126/scitranslmed.3008782. PMID:25320235 doi:https://dx.doi.org/10.1126/scitranslmed.3008782
