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Adv Appl Bioinform Chem. 2018 Oct 15;11:1-8. doi: 10.2147/AABC.S177206. eCollection 2018.

Computational analysis of ligand-receptor interactions in wild-type and mutant erythropoietin complexes.

Author information

1
Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069, USA, Samuel.Sathyanesan@usd.edu.

Abstract

Background:

Erythropoietin (EPO), a pleiotropic cytokine, binds to its receptor (EPOR) in bone marrow, activating a signaling cascade that results in red blood cell proliferation. A recently discovered naturally occurring EPO mutation (R150Q) at active site 1 (AS1) of the protein was shown to attenuate its canonical downstream signaling, eliminating its hematopoietic effects and causing a fatal anemia. The purpose of this work was to analyze the EPO-EPOR complex computationally to provide a structural explanation for this signaling change.

Materials and methods:

Computational structural biology analyses and molecular dynamics simulations were used to determine key interaction differences between the R150Q mutant and the wild-type form of EPO. Both were compared to another variant mutated at the same position, R150E, which also lacks hematopoietic activity.

Results:

The ligand-receptor interactions of the R150Q and R150E mutants showed significant variations in how they interacted with EPOR at AS1 of the EPO-EPOR complex. Both lost specific reported salt bridges previously associated with full complex activation.

Conclusion:

This work describes how the ligand-receptor interactions at AS1 of the EPO- EPOR complex respond to mutations at the 150th position. The interactions at AS1 were used to propose a potential mechanism by which the binding of EPO to the extracellular domain of EPOR influences its cytosolic domain and the resulting signaling cascade.

KEYWORDS:

binding affinity; hematopoiesis; molecular dynamics; signaling cascade

Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

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