Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Lipids Shape the Electron Acceptor-Binding Site of the Peripheral Membrane Protein Dihydroorotate Dehydrogenase
Uppsala Univ, Dept Chem BMC, Box 576, S-75123 Uppsala, Sweden..
Univ Oxford, Dept Chem, Phys & Theoret Chem Lab, South Parks Rd, Oxford OX1 3QZ, England..
Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Nobels Vag 16, S-17177 Stockholm, Sweden..
Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Nobels Vag 16, S-17177 Stockholm, Sweden..
Show others and affiliations
2018 (English)In: Cell Chemical Biology, ISSN 2451-9456, E-ISSN 2451-9448, Vol. 25, no 3, p. 309-+Article in journal (Refereed) Published
Abstract [en]

The interactions between proteins and biological membranes are important for drug development, but remain notoriously refractory to structural investigation. We combine non-denaturing mass spectrometry (MS) with molecular dynamics (MD) simulations to unravel the connections among cofactor, lipid, and inhibitor binding in the peripheral membrane protein dihydroorotate dehydrogenase (DHODH), a key anticancer target. Interrogation of intact DHODH complexes by MS reveals that phospholipids bind via their charged head groups at a limited number of sites, while binding of the inhibitor brequinar involves simultaneous association with detergent molecules. MD simulations show that lipids support flexible segments in the membrane-binding domain and position the inhibitor and electron acceptor-binding site away from the membrane surface, similar to the electron acceptor-binding site in respiratory chain complex I. By complementing MS with MD simulations, we demonstrate how a peripheral membrane protein uses lipids to modulate its structure in a similar manner as integral membrane proteins.

Place, publisher, year, edition, pages
CELL PRESS , 2018. Vol. 25, no 3, p. 309-+
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:kth:diva-225720DOI: 10.1016/j.chembiol.2017.12.012ISI: 000427600400011PubMedID: 29358052Scopus ID: 2-s2.0-85040560845OAI: oai:DiVA.org:kth-225720DiVA, id: diva2:1196609
Funder
Swedish National Infrastructure for Computing (SNIC), SNIC 2017/7-15; SNIC 2017/1-188Swedish Foundation for Strategic Research Swedish Research Council, 2015-00559Swedish Cancer SocietySwedish Childhood Cancer Foundation
Note

QC 20180410

Available from: 2018-04-10 Created: 2018-04-10 Last updated: 2018-04-10Bibliographically approved

Open Access in DiVA

No full text in DiVA

Other links

Publisher's full textPubMedScopus

Search in DiVA

By author/editor
Olsson, Anders
By organisation
Science for Life Laboratory, SciLifeLabProtein Science
In the same journal
Cell Chemical Biology
Biological Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 20 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf