Abstract
Human odorant binding proteins (OBPs) are lipocalins proposed to function by carrying small molecules through aqueous environments to olfactory receptors. In contrast to previous reports, results from fluorescence assays herein show that ligands bind to OBP-2a with two affinities, one with a micromolar and one with a nanomolar equilibrium dissociation constant. Computational modeling of the protein reveals these states could be associated with two binding sites for hydrophobic and/or aromatic molecules, and is not dependent on functional groups such as aldehyde moieties. Small-molecule hydrophobic uremic toxins like p-cresol were found to effectively compete for binding to OBP-2a nearly as well as traditional odorants like vanillin. The results support a possible molecular mechanism for interference of uremic toxins that could result in the impaired olfactory sensitivity described for patients with advanced renal disease.
Highlights
Human olfaction is characterized by the ability to detect and discriminate between thousands of distinct odors; the specific molecular mechanism by which much of the pathway occurs is not elucidated
We propose that in CKD and ESRD patients, hydrophobic uremic toxins may bind to odorant binding proteins (OBPs) and related lipocalins, saturating the olfactory signaling pathway at this level and inhibiting OBPs from participating in normal transport and delivery functions for other odorants to olfactory receptors
Previous reports were based on a construct of OBP-2a containing Cys114 to Ser and Thr163 to Ala that was made to prevent heterogeneity of the product due to post-translational alkylation or O-linked glycosylation when expressed in Pichia pastoris [4]
Summary
Human olfaction is characterized by the ability to detect and discriminate between thousands of distinct odors; the specific molecular mechanism by which much of the pathway occurs is not elucidated. Page 4 of 7 analysis for NPN only yielded one affinity state; NPN (with a three-ringed aromatic structure) may occupy more volume in the hydrophobic binding pocket of OBP-2a, being stericly hindered from having more than one mode of interaction with the protein, in contrast to the two modes of binding seen for smaller ligands.
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