2P4E

Crystal Structure of PCSK9

Summary for 2P4E

• Entry DOI: 10.2210/pdb2p4e/pdb
• Descriptor: Proprotein convertase subtilisin/kexin type 9, MERCURY (II) ION (3 entities in total)
• Functional Keywords: protease, subtilisin, ldl receptor, ldl, endocytosis, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: Q8NBP7
• Total number of polymer chains: 2
• Total formula weight: 149323.76

Authors

Cunningham, D.,Danley, D.E.,Geoghegan, F.K.,Griffor, M.C.,Hawkins, J.L.,Qiu, X. (deposition date: 2007-03-12, release date: 2007-04-10, Last modification date: 2024-10-30)

Primary citation

Cunningham, D.,Danley, D.E.,Geoghegan, K.F.,Griffor, M.C.,Hawkins, J.L.,Subashi, T.A.,Varghese, A.H.,Ammirati, M.J.,Culp, J.S.,Hoth, L.R.,Mansour, M.N.,McGrath, K.M.,Seddon, A.P.,Shenolikar, S.,Stutzman-Engwall, K.J.,Warren, L.C.,Xia, D.,Qiu, X.
Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia.
Nat.Struct.Mol.Biol., 14:413-419, 2007

PubMed Abstract: 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.

PubMed: 17435765
DOI: 10.1038/nsmb1235

Experimental method

X-RAY DIFFRACTION (1.98 Å)