2p4e
From Proteopedia
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==Overview== | ==Overview== | ||
| - | Proprotein convertase subtilisin kexin type 9 (PCSK9) lowers the abundance | + | Proprotein convertase subtilisin kexin type 9 (PCSK9) lowers the abundance of surface low-density lipoprotein (LDL) receptor through an undefined mechanism. The structure of human PCSK9 shows the subtilisin-like catalytic site blocked by the prodomain in a noncovalent complex and inaccessible to exogenous ligands, and that the C-terminal domain has a novel fold. Biosensor studies show that PCSK9 binds the extracellular domain of LDL receptor with K(d) = 170 nM at the neutral pH of plasma, but with a K(d) as low as 1 nM at the acidic pH of endosomes. The D374Y gain-of-function mutant, associated with hypercholesterolemia and early-onset cardiovascular disease, binds the receptor 25 times more tightly than wild-type PCSK9 at neutral pH and remains exclusively in a high-affinity complex at the acidic pH. PCSK9 may diminish LDL receptors by a mechanism that requires direct binding but not necessarily receptor proteolysis. |
| + | |||
| + | ==Disease== | ||
| + | Known diseases associated with this structure: Hypercholesterolemia, familial, 3 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=607786 607786]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Cunningham, D.]] | [[Category: Cunningham, D.]] | ||
| - | [[Category: Danley, D | + | [[Category: Danley, D E.]] |
| - | [[Category: Geoghegan, F | + | [[Category: Geoghegan, F K.]] |
| - | [[Category: Griffor, M | + | [[Category: Griffor, M C.]] |
| - | [[Category: Hawkins, J | + | [[Category: Hawkins, J L.]] |
[[Category: Qiu, X.]] | [[Category: Qiu, X.]] | ||
[[Category: HG]] | [[Category: HG]] | ||
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[[Category: subtilisin]] | [[Category: subtilisin]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:25:42 2008'' |
Revision as of 16:25, 21 February 2008
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Crystal Structure of PCSK9
Contents |
Overview
Proprotein convertase subtilisin kexin type 9 (PCSK9) lowers the abundance of surface low-density lipoprotein (LDL) receptor through an undefined mechanism. The structure of human PCSK9 shows the subtilisin-like catalytic site blocked by the prodomain in a noncovalent complex and inaccessible to exogenous ligands, and that the C-terminal domain has a novel fold. Biosensor studies show that PCSK9 binds the extracellular domain of LDL receptor with K(d) = 170 nM at the neutral pH of plasma, but with a K(d) as low as 1 nM at the acidic pH of endosomes. The D374Y gain-of-function mutant, associated with hypercholesterolemia and early-onset cardiovascular disease, binds the receptor 25 times more tightly than wild-type PCSK9 at neutral pH and remains exclusively in a high-affinity complex at the acidic pH. PCSK9 may diminish LDL receptors by a mechanism that requires direct binding but not necessarily receptor proteolysis.
Disease
Known diseases associated with this structure: Hypercholesterolemia, familial, 3 OMIM:[607786]
About this Structure
2P4E is a Single protein structure of sequence from Homo sapiens with as ligand. Full crystallographic information is available from OCA.
Reference
Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia., Cunningham D, Danley DE, Geoghegan KF, Griffor MC, Hawkins JL, Subashi TA, Varghese AH, Ammirati MJ, Culp JS, Hoth LR, Mansour MN, McGrath KM, Seddon AP, Shenolikar S, Stutzman-Engwall KJ, Warren LC, Xia D, Qiu X, Nat Struct Mol Biol. 2007 May;14(5):413-9. Epub 2007 Apr 15. PMID:17435765
Page seeded by OCA on Thu Feb 21 18:25:42 2008
Categories: Homo sapiens | Single protein | Cunningham, D. | Danley, D E. | Geoghegan, F K. | Griffor, M C. | Hawkins, J L. | Qiu, X. | HG | Endocytosis | Ldl | Ldl receptor | Protease | Subtilisin
