uu.seUppsala universitets publikasjoner
Endre søk
RefereraExporteraLink to record
Permanent link

Direct link
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Catalytic Stimulation by Restrained Active-Site Floppiness-The Case of High Density Lipoprotein-Bound Serum Paraoxonase-1
Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
Vise andre og tillknytning
2015 (engelsk)Inngår i: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 427, nr 6, s. 1359-1374Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Despite the abundance of membrane-associated enzymes, the mechanism by which membrane binding stabilizes these enzymes and stimulates their catalysis remains largely unknown. Serum paraoxonase-1 (PON1) is a lipophilic lactonase whose stability and enzymatic activity are dramatically stimulated when associated with high-density lipoprotein (HDL) particles. Our mutational and structural analyses, combined with empirical valence bond simulations, reveal a network of hydrogen bonds that connect HDL binding residues with Asn168-a key catalytic residue residing >15 angstrom from the HDL contacting interface. This network ensures precise alignment of N168, which, in turn, ligates PON1's catalytic calcium and aligns the lactone substrate for catalysis. HDL binding restrains the overall motion of the active site and particularly of N168, thus reducing the catalytic activation energy barrier. We demonstrate herein that disturbance of this network, even at its most far-reaching periphery, undermines PON1's activity. Membrane binding thus immobilizes long-range interactions via second- and third-shell residues that reduce the active site's floppiness and pre-organize the catalytic residues. Although this network is critical for efficient catalysis, as demonstrated here, unraveling these long-rage interaction networks is challenging, let alone their implementation in artificial enzyme design.

sted, utgiver, år, opplag, sider
2015. Vol. 427, nr 6, s. 1359-1374
Emneord [en]
PON1, 192 polymorphism, interfacial activation, enzyme dynamics, HDL
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-251998DOI: 10.1016/j.jmb.2015.01.013ISI: 000351798700011PubMedID: 25644661OAI: oai:DiVA.org:uu-251998DiVA, id: diva2:810772
Forskningsfinansiär
Knut and Alice Wallenberg Foundation, 2010-5026Swedish Research CouncilSwedish National Infrastructure for Computing (SNIC), 2013/26-1Tilgjengelig fra: 2015-05-08 Laget: 2015-04-28 Sist oppdatert: 2017-12-04

Open Access i DiVA

Fulltekst mangler i DiVA

Andre lenker

Forlagets fulltekstPubMed

Personposter BETA

Szeler, KlaudiaKamerlin, Lynn Shina C.

Søk i DiVA

Av forfatter/redaktør
Szeler, KlaudiaKamerlin, Lynn Shina C.
Av organisasjonen
I samme tidsskrift
Journal of Molecular Biology

Søk utenfor DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric

doi
pubmed
urn-nbn
Totalt: 854 treff
RefereraExporteraLink to record
Permanent link

Direct link
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf