7KFA

PCSK9 in complex with PCSK9i a 13mer cyclic peptide LDLR disruptor

Summary for 7KFA

• Entry DOI: 10.2210/pdb7kfa/pdb
• Descriptor: Proprotein convertase subtilisin/kexin type 9 Propeptide, Proprotein convertase subtilisin/kexin type 9, 1-[2,6,10.14-TETRAMETHYL-HEXADECAN-16-YL]-2-[2,10,14-TRIMETHYLHEXADECAN-16-YL]GLYCEROL, ... (5 entities in total)
• Functional Keywords: pro-protein convertase, coronary heart disease, hypercholesterolemia, low density lipoprotein receptor, autocatalytic cleavage, cholesterol metabolism, disease mutation, glycoprotein, hydrolase, lipid metabolism, phosphorylation, protease, secreted, serine protease, steroid metabolism, zymogen, lipid transport
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 73966.38

Authors

Chopra, R.,Xu, M.,Spraggon, G. (deposition date: 2020-10-13, release date: 2021-11-10, Last modification date: 2023-10-18)

Primary citation

Brousseau, M.E.,Clairmont, K.B.,Spraggon, G.,Flyer, A.N.,Golosov, A.A.,Grosche, P.,Amin, J.,Andre, J.,Burdick, D.,Caplan, S.,Chen, G.,Chopra, R.,Ames, L.,Dubiel, D.,Fan, L.,Gattlen, R.,Kelly-Sullivan, D.,Koch, A.W.,Lewis, I.,Li, J.,Liu, E.,Lubicka, D.,Marzinzik, A.,Nakajima, K.,Nettleton, D.,Ottl, J.,Pan, M.,Patel, T.,Perry, L.,Pickett, S.,Poirier, J.,Reid, P.C.,Pelle, X.,Seepersaud, M.,Subramanian, V.,Vera, V.,Xu, M.,Yang, L.,Yang, Q.,Yu, J.,Zhu, G.,Monovich, L.G.
Identification of a PCSK9-LDLR disruptor peptide with in vivo function.
Cell Chem Biol, 29:249-, 2022

PubMed Abstract: Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates plasma low-density lipoprotein cholesterol (LDL-C) levels by promoting hepatic LDL receptor (LDLR) degradation. Therapeutic antibodies that disrupt PCSK9-LDLR binding reduce LDL-C concentrations and cardiovascular disease risk. The epidermal growth factor precursor homology domain A (EGF-A) of the LDLR serves as a primary contact with PCSK9 via a flat interface, presenting a challenge for identifying small molecule PCSK9-LDLR disruptors. We employ an affinity-based screen of 10in vitro-translated macrocyclic peptides to identify high-affinity PCSK9 ligands that utilize a unique, induced-fit pocket and partially disrupt the PCSK9-LDLR interaction. Structure-based design led to molecules with enhanced function and pharmacokinetic properties (e.g., PCSK9i). In mice, PCSK9i reduces plasma cholesterol levels and increases hepatic LDLR density in a dose-dependent manner. PCSK9i functions by a unique, allosteric mechanism and is the smallest molecule identified to date with in vivo PCSK9-LDLR disruptor function.

PubMed: 34547225
DOI: 10.1016/j.chembiol.2021.08.012

Experimental method

X-RAY DIFFRACTION (2.45 Å)