3bps: Difference between revisions
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|PDB= 3bps |SIZE=350|CAPTION= <scene name='initialview01'>3bps</scene>, resolution 2.41Å | |PDB= 3bps |SIZE=350|CAPTION= <scene name='initialview01'>3bps</scene>, resolution 2.41Å | ||
|SITE= <scene name='pdbsite=AC1:Ca+Binding+Site+For+Residue+E+1'>AC1</scene> | |SITE= <scene name='pdbsite=AC1:Ca+Binding+Site+For+Residue+E+1'>AC1</scene> | ||
|LIGAND= <scene name='pdbligand=CA:CALCIUM ION'>CA</scene> | |LIGAND= <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene> | ||
|ACTIVITY= | |ACTIVITY= | ||
|GENE= PCSK9, NARC1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]), LDLR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= PCSK9, NARC1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]), LDLR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
|DOMAIN= | |||
|RELATEDENTRY= | |||
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3bps FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3bps OCA], [http://www.ebi.ac.uk/pdbsum/3bps PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=3bps RCSB]</span> | |||
}} | }} | ||
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==Overview== | ==Overview== | ||
Proprotein convertase subtilisin/kexin type 9 (PCSK9) posttranslationally regulates hepatic low-density lipoprotein receptors (LDLRs) by binding to LDLRs on the cell surface, leading to their degradation. The binding site of PCSK9 has been localized to the epidermal growth factor-like repeat A (EGF-A) domain of the LDLR. Here, we describe the crystal structure of a complex between PCSK9 and the EGF-A domain of the LDLR. The binding site for the LDLR EGF-A domain resides on the surface of PCSK9's subtilisin-like catalytic domain containing Asp-374, a residue for which a gain-of-function mutation (Asp-374-Tyr) increases the affinity of PCSK9 toward LDLR and increases plasma LDL-cholesterol (LDL-C) levels in humans. The binding surface on PCSK9 is distant from its catalytic site, and the EGF-A domain makes no contact with either the C-terminal domain or the prodomain. Point mutations in PCSK9 that altered key residues contributing to EGF-A binding (Arg-194 and Phe-379) greatly diminished binding to the LDLR's extracellular domain. The structure of PCSK9 in complex with the LDLR EGF-A domain defines potential therapeutic target sites for blocking agents that could interfere with this interaction in vivo, thereby increasing LDLR function and reducing plasma LDL-C levels. | Proprotein convertase subtilisin/kexin type 9 (PCSK9) posttranslationally regulates hepatic low-density lipoprotein receptors (LDLRs) by binding to LDLRs on the cell surface, leading to their degradation. The binding site of PCSK9 has been localized to the epidermal growth factor-like repeat A (EGF-A) domain of the LDLR. Here, we describe the crystal structure of a complex between PCSK9 and the EGF-A domain of the LDLR. The binding site for the LDLR EGF-A domain resides on the surface of PCSK9's subtilisin-like catalytic domain containing Asp-374, a residue for which a gain-of-function mutation (Asp-374-Tyr) increases the affinity of PCSK9 toward LDLR and increases plasma LDL-cholesterol (LDL-C) levels in humans. The binding surface on PCSK9 is distant from its catalytic site, and the EGF-A domain makes no contact with either the C-terminal domain or the prodomain. Point mutations in PCSK9 that altered key residues contributing to EGF-A binding (Arg-194 and Phe-379) greatly diminished binding to the LDLR's extracellular domain. The structure of PCSK9 in complex with the LDLR EGF-A domain defines potential therapeutic target sites for blocking agents that could interfere with this interaction in vivo, thereby increasing LDLR function and reducing plasma LDL-C levels. | ||
==Disease== | |||
Known disease associated with this structure: Hypercholesterolemia, familial OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606945 606945]] | |||
==About this Structure== | ==About this Structure== | ||
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[[Category: Protein complex]] | [[Category: Protein complex]] | ||
[[Category: Kwon, H J.]] | [[Category: Kwon, H J.]] | ||
[[Category: alternative splicing]] | [[Category: alternative splicing]] | ||
[[Category: autocatalytic cleavage]] | [[Category: autocatalytic cleavage]] | ||
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[[Category: zymogen]] | [[Category: zymogen]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 05:28:05 2008'' | ||
Revision as of 05:28, 31 March 2008
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| , resolution 2.41Å | |||||||
|---|---|---|---|---|---|---|---|
| Sites: | |||||||
| Ligands: | |||||||
| Gene: | PCSK9, NARC1 (Homo sapiens), LDLR (Homo sapiens) | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
PCSK9:EGF-A complex
OverviewOverview
Proprotein convertase subtilisin/kexin type 9 (PCSK9) posttranslationally regulates hepatic low-density lipoprotein receptors (LDLRs) by binding to LDLRs on the cell surface, leading to their degradation. The binding site of PCSK9 has been localized to the epidermal growth factor-like repeat A (EGF-A) domain of the LDLR. Here, we describe the crystal structure of a complex between PCSK9 and the EGF-A domain of the LDLR. The binding site for the LDLR EGF-A domain resides on the surface of PCSK9's subtilisin-like catalytic domain containing Asp-374, a residue for which a gain-of-function mutation (Asp-374-Tyr) increases the affinity of PCSK9 toward LDLR and increases plasma LDL-cholesterol (LDL-C) levels in humans. The binding surface on PCSK9 is distant from its catalytic site, and the EGF-A domain makes no contact with either the C-terminal domain or the prodomain. Point mutations in PCSK9 that altered key residues contributing to EGF-A binding (Arg-194 and Phe-379) greatly diminished binding to the LDLR's extracellular domain. The structure of PCSK9 in complex with the LDLR EGF-A domain defines potential therapeutic target sites for blocking agents that could interfere with this interaction in vivo, thereby increasing LDLR function and reducing plasma LDL-C levels.
DiseaseDisease
Known disease associated with this structure: Hypercholesterolemia, familial OMIM:[606945]
About this StructureAbout this Structure
3BPS is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Molecular basis for LDL receptor recognition by PCSK9., Kwon HJ, Lagace TA, McNutt MC, Horton JD, Deisenhofer J, Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):1820-5. Epub 2008 Feb 4. PMID:18250299
Page seeded by OCA on Mon Mar 31 05:28:05 2008
Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
OCA- Pages with broken file links
- Homo sapiens
- Protein complex
- Kwon, H J.
- Alternative splicing
- Autocatalytic cleavage
- Calcium
- Cholesterol metabolism
- Coated pit
- Disease mutation
- Egf-like domain
- Endocytosis
- Glycoprotein
- Host-virus interaction
- Hydrolase
- Hydrolase/lipid transport complex
- Ldl receptor
- Lipid metabolism
- Lipid transport
- Membrane
- Pcsk9
- Phosphoprotein
- Polymorphism
- Protease
- Secreted
- Serine protease
- Steroid metabolism
- Transmembrane
- Transport
- Zymogen