Journal Article

FZJ-2019-04708

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Basal Histamine H4 Receptor Activation: Agonist Mimicry by the Diphenylalanine Motif

Wifling, D. ; Pfleger, C. ; Kaindl, J. ; Ibrahim, P. ; Kling, R. ; Buschauer, A. ; Gohlke, H. (Corresponding author)FZJ* ; Clark, T. (Corresponding author)

2019
Wiley-VCH Weinheim

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Please use a persistent id in citations: doi:10.1002/chem.201902801

Abstract: Histamine H4 receptor (H4R) orthologues are G‐protein coupled receptors (GPCRs) that exhibit species‐dependent basal activity: In contrast to the basally inactive mouse H4R (mH4R), human H4R (hH4R) shows a high degree of basal activity. We have performed long‐time‐scale molecular‐dynamics simulations and rigidity analyses on wild‐type hH4R, the experimentally characterized hH4R variants S179M, F169V, F169V+S179M, F168A, and on mH4R to investigate the molecular nature of differential basal activity. H4R variant‐dependent differences between essential motifs of GPCR activation and structural stabilities correlate with experimentally determined basal activities and provide a molecular explanation for the differences in basal activation. Strikingly, during the MD simulations, F16945.55 dips into the orthosteric binding pocket only in the case of hH4R, thus adopting the role of an agonist and contributing to the stabilization of the active state. The results shed new light on the molecular mechanism of basal H4R activation that are of importance for other GPCRs.

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Contributing Institute(s):

1. John von Neumann - Institut für Computing (NIC)
2. Jülich Supercomputing Center (JSC)
3. Strukturbiochemie (ICS-6)

Research Program(s):

1. 511 - Computational Science and Mathematical Methods (POF3-511) (POF3-511)
2. Forschergruppe Gohlke (hkf7_20170501) (hkf7_20170501)

Appears in the scientific report 2019

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Database coverage:
; Clarivate Analytics Master Journal List ; Current Contents - Physical, Chemical and Earth Sciences ; Ebsco Academic Search ; IF >= 5 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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