Molecular Modeling and Site-Specific Mutagenesis of the Histamine-Binding Site of the Histamine H₄Receptor

Abstract

The histamine H 4 receptor is a novel G-protein-coupled receptor with a unique pharmacological profile. The distribution of H 4 mRNA suggests that it may play a role in the regulation of immune function, particularly with respect to allergy and asthma. To define the histamine-binding site of this receptor, molecular modeling and site-directed mutagenesis were used to predict and alter amino acids residing in the histaminebinding pocket. The effects of these alterations on histamine binding and receptor activation were then assessed. (6.52) in TM6 play a role in receptor activation but are not involved in histamine binding. Taken together, these data indicate that although histamine seems to bind to the H 4 receptor in a fashion similar to that predicted for the other histamine receptor subtypes, there are also important differences that can probably be exploited for the discovery of novel H 4 -selective compounds.

Structure-based discovery and binding site analysis of histamine receptor ligands

“…During the simulations, the interaction between histamine's imidazole NH and Asp94(3.32) broke, however, both residues formed strong interactions with Glu165(5.29) resulting in a stable triad. Interestingly, histamine formed an interaction with Asn147(4.57) that was previously proved to be important in hH4R activation [12]. When simulating the histamine-H4R complex, we found several signs of GPCR activation including the intracellular part of TM6 moved outward relative to TM3 and TM7.…”

“…After the discovery of the H4 receptor, one of the earliest modeling studies was published by Shin et al [12]. In this paper, a homology model of human H4R was constructed based on the bovine rhodopsin structure.…”

“…The high resolution rhodopsin structure allowed the construction of homology models for the two new histamine receptors H3 [11] and H4 [12] as well.…”

Construction and Retrospective Validation of Structure-Based Virtual Screening Protocols to Identify Potent Ligands for Human Adrenergic Beta-2 Receptor

“…Unfortunately, the information of key interactions is available only for a few drug targets. The key interaction used in the SBVS campaigns on crystal structure of HRH1 was identified from previous Site-Directed Mutagenesis (SDM) studies and chemogenomic analysis Shin et al, 2002;Surgand et al, 2006). Besides SDM studies and chemogenomic analysis, some computer-aided strategies could be employed in order to obtain information on key interactions that can assist the improvement of SBVS quality. )…”

From Receptors to Ligands: Fragment-assisted Drug Design for GPCRs Applied to the Discovery of H3 and H4 Receptor Antagonists

“…The rotamer library of GOLD [72] (Cambridge Crystallographic Data Centre) was used to is vital for driving the development of the next generation of new H3 or H4 antagonists. Recently several studies were conducted to address this problem, involving in-silico guided site directed mutagenesis data (SDM) [16,17]. This data shows that key residues, responsible for antagonist binding to H3 receptors are D114 L showed an average of a ~10 fold decrease in potency for a series of clobenpropit derivatives (selective H4 antagonists) to H4 [18].…”