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1000 Titel
  • A Single Glycine-Alanine Exchange Directs Ligand Specificity of the Elephant Progestin Receptor
1000 Autor/in
  1. Wierer, Michael |
  2. Schrey, Anna K. |
  3. Kühne, Ronald |
  4. Ulbrich, Susanne E. |
  5. Meyer, Heinrich H. D. |
1000 Erscheinungsjahr 2012
1000 LeibnizOpen
1000 Art der Datei
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2012-11-27
1000 Erschienen in
1000 Quellenangabe
  • 7(11):e50350
1000 FRL-Sammlung
1000 Copyrightjahr
  • 2012
1000 Lizenz
1000 Verlagsversion
  • http://dx.doi.org/10.1371/journal.pone.0050350 |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3507690/ |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • The primary gestagen of elephants is 5α-dihydroprogesterone (DHP), which is unlike all other mammals studied until now. The level of DHP in elephants equals that of progesterone in other mammals, and elephants are able to bind DHP with similar affinity to progesterone indicating a unique ligand-binding specificity of the elephant progestin receptor (PR). Using site-directed mutagenesis in combination with in vitro binding studies we here report that this change in specificity is due to a single glycine to alanine exchange at position 722 (G722A) of PR, which specifically increases DHP affinity while not affecting binding of progesterone. By conducting molecular dynamics simulations comparing human and elephant PR ligand-binding domains (LBD), we observed that the alanine methyl group at position 722 is able to push the DHP A-ring into a position similar to progesterone. In the human PR, the DHP A-ring position is twisted towards helix 3 of PR thereby disturbing the hydrogen bond pattern around the C3-keto group, resulting in a lower binding affinity. Furthermore, we observed that the elephant PR ligand-binding pocket is more rigid than the human analogue, which probably explains the higher affinity towards both progesterone and DHP. Interestingly, the G722A substitution is not elephant-specific, rather it is also present in five independent lineages of mammalian evolution, suggesting a special role of the substitution for the development of distinct mammalian gestagen systems.
1000 Sacherschließung
lokal Sequence alignment
lokal Horses
lokal Progesterone
lokal Hydrogen bonding
lokal Microbial evolution
lokal Elephants
lokal Steroid hormones
lokal Amino acid substitution
1000 Fachgruppe
  1. Biologie |
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
  1. https://frl.publisso.de/adhoc/creator/IFdpZXJlciwgTWljaGFlbA==|https://frl.publisso.de/adhoc/creator/IFNjaHJleSwgQW5uYSBLLg==|https://frl.publisso.de/adhoc/creator/IEvDvGhuZSwgUm9uYWxk|https://frl.publisso.de/adhoc/creator/IFVsYnJpY2gsIFN1c2FubmUgRS4=|https://frl.publisso.de/adhoc/creator/IE1leWVyLCBIZWlucmljaCBILiBELg==
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1000 Oai Id
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