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Rosetta Broker for membrane protein structure prediction: concentrative nucleoside transporter 3 and corticotropin-releasing factor receptor 1 test cases

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cris.lastimport.scopus2024-02-12T19:54:31Z
dc.abstract.enBackground: Membrane proteins are difficult targets for structure prediction due to the limited structural data deposited in Protein Data Bank. Most computational methods for membrane protein structure prediction are based on the comparative modeling. There are only few de novo methods targeting that distinct protein family. In this work an example of such de novo method was used to structurally and functionally characterize two representatives of distinct membrane proteins families of solute carrier transporters and G protein-coupled receptors. The well-known Rosetta program and one of its protocols named Broker was used in two test cases. The first case was de novo structure prediction of three N-terminal transmembrane helices of the human concentrative nucleoside transporter 3 (hCNT3) homotrimer belonging to the solute carrier 28 family of transporters (SLC28). The second case concerned the large scale refinement of transmembrane helices of a homology model of the corticotropin-releasing factor receptor 1 (CRFR1) belonging to the G protein-coupled receptors family. Results: The inward-facing model of the hCNT3 homotrimer was used to propose the functional impact of its single nucleotide polymorphisms. Additionally, the 100 ns molecular dynamics simulation of the unliganded hCNT3 model confirmed its validity and revealed mobility of the selected binding site and homotrimer interface residues. The large scale refinement of transmembrane helices of the CRFR1 homology model resulted in the significant improvement of its accuracy with respect to the crystal structure of CRFR1, especially in the binding site area. Consequently, the antagonist CP-376395 could be docked with Autodock VINA to the CRFR1 model without any steric clashes. Conclusions: The presented work demonstrated that Rosetta Broker can be a versatile tool for solving various issues referring to protein biology. Two distinct examples of de novo membrane protein structure prediction presented here provided important insights into three major areas of protein biology. Namely, the dynamics of the inward-facing hCNT3 homotrimer system, the structural changes of the CRFR1 receptor upon the antagonist binding and finally, the role of single nucleotide polymorphisms in both, hCNT3 and CRFR1 proteins, were investigated.
dc.affiliationUniwersytet Warszawski
dc.contributor.authorLatek, Dorota
dc.date.accessioned2024-01-25T19:28:21Z
dc.date.available2024-01-25T19:28:21Z
dc.date.copyright2017-08-03
dc.date.issued2017
dc.description.accesstimeAT_PUBLICATION
dc.description.financeNie dotyczy
dc.description.number1
dc.description.versionFINAL_PUBLISHED
dc.description.volume17
dc.identifier.doi10.1186/S12900-017-0078-8
dc.identifier.issn1472-6807
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/118769
dc.languageeng
dc.pbn.affiliationbiological sciences
dc.relation.ispartofBMC Structural Biology
dc.relation.pagesart.no. 8
dc.rightsCC-BY
dc.sciencecloudnosend
dc.subject.enMembrane proteins
dc.subject.enSolute carrier transporters
dc.subject.enSLC28
dc.subject.enConcentrative nucleoside transporter 3
dc.subject.enSingle nucleotide polymorphisms
dc.subject.enG protein-coupled receptors
dc.subject.enCorticotropin-releasing factor receptor 1
dc.subject.enRosetta Broker
dc.subject.enGPCRM
dc.subject.enNAMD
dc.titleRosetta Broker for membrane protein structure prediction: concentrative nucleoside transporter 3 and corticotropin-releasing factor receptor 1 test cases
dc.typeJournalArticle
dspace.entity.typePublication