3bps

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
(New page: 200px<br /><applet load="3bps" size="350" color="white" frame="true" align="right" spinBox="true" caption="3bps, resolution 2.41&Aring;" /> '''PCSK9:EGF-A complex'...)
Line 4: Line 4:
==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.
==About this Structure==
==About this Structure==
Line 10: Line 10:
==Reference==
==Reference==
-
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 4;. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=18250299 18250299]
+
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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=18250299 18250299]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Protein complex]]
[[Category: Protein complex]]
-
[[Category: Kwon, H.J.]]
+
[[Category: Kwon, H J.]]
[[Category: CA]]
[[Category: CA]]
[[Category: alternative splicing]]
[[Category: alternative splicing]]
Line 42: Line 42:
[[Category: zymogen]]
[[Category: zymogen]]
-
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Feb 13 08:23:55 2008''
+
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 19:07:00 2008''

Revision as of 17:07, 21 February 2008

Image:3bps.jpg

3bps, resolution 2.41Å

Drag the structure with the mouse to rotate

PCSK9:EGF-A complex

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.

About this Structure

3BPS is a Protein complex structure of sequences from Homo sapiens with as ligand. Known structural/functional Site: . Full crystallographic information is available from OCA.

Reference

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 Thu Feb 21 19:07:00 2008

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3bps"
Personal tools