Do all X-ray structures of protein-ligand complexes represent functional states? EPOR, a case study

Corbett, Michael S. P., Mark, Alan E. and Poger, David (2017) Do all X-ray structures of protein-ligand complexes represent functional states? EPOR, a case study. Biophysical Journal, 112 4: 595-604. doi:10.1016/j.bpj.2016.12.042


Author Corbett, Michael S. P.
Mark, Alan E.
Poger, David
Title Do all X-ray structures of protein-ligand complexes represent functional states? EPOR, a case study
Journal name Biophysical Journal   Check publisher's open access policy
ISSN 0006-3495
1542-0086
Publication date 2017-02-28
Sub-type Article (original research)
DOI 10.1016/j.bpj.2016.12.042
Open Access Status Not yet assessed
Volume 112
Issue 4
Start page 595
End page 604
Total pages 10
Place of publication St. Louis, MO, United States
Publisher Cell Press
Collection year 2018
Language eng
Abstract Based on differences between the x-ray crystal structures of ligand-bound and unbound forms, the activation of the erythropoietin receptor (EPOR) was initially proposed to involve a cross-action scissorlike motion. However, the validity of the motions involved in the scissorlike model has been recently challenged. Here, atomistic molecular dynamics simulations are used to examine the structure of the extracellular domain of the EPOR dimer in the presence and absence of erythropoietin and a series of agonistic or antagonistic mimetic peptides free in solution. The simulations suggest that in the absence of crystal packing effects, the EPOR chains in the different dimers adopt very similar conformations with no clear distinction between the agonist and antagonist-bound complexes. This questions whether the available x-ray crystal structures of EPOR truly represent active or inactive conformations. The study demonstrates the difficulty in using such structures to infer a mechanism of action, especially in the case of membrane receptors where just part of the structure has been considered in addition to potential confounding effects that arise from the comparison of structures in a crystal as opposed to a membrane environment. The work highlights the danger of assigning functional significance to small differences between structures of proteins bound to different ligands in a crystal environment without consideration of the effects of the crystal lattice and thermal motion.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
School of Chemistry and Molecular Biosciences
Institute for Molecular Bioscience - Publications
 
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Created: Fri, 10 Mar 2017, 15:05:21 EST by Mrs Louise Nimwegen on behalf of School of Chemistry & Molecular Biosciences