Abstract：
:Evidence suggests that many G protein-coupled receptors (GPCRs) are bound together forming dimers. The implications of dimerisation for cellular signalling outcomes, and ultimately drug discovery and therapeutics, remain unclear. Consideration of ligand binding and signalling via receptor dimers is therefore required as an addition to classical receptor theory, which is largely built on assumptions of monomeric receptors. A key factor in developing theoretical models of dimer signalling is cooperativity across the dimer, whereby binding of a ligand to one protomer affects the binding of a ligand to the other protomer. Here, we present and analyse linear models for one-ligand and two-ligand binding dynamics at homodimerised receptors, as an essential building block in the development of dimerised receptor theory. For systems at equilibrium, we compute analytical solutions for total bound labelled ligand and derive conditions on the cooperativity factors under which multiphasic log dose-response curves are expected. This could help explain data extracted from pharmacological experiments that do not fit to the standard Hill curves that are often used in this type of analysis. For the time-dependent problems, we also obtain analytical solutions. For the single-ligand case, the construction of the analytical solution is straightforward; it is bi-exponential in time, sharing a similar structure to the well-known monomeric competition dynamics of Motulsky-Mahan. We suggest that this model is therefore practically usable by the pharmacologist towards developing insights into the potential dynamics and consequences of dimerised receptors.
journal_name
Bull Math Bioljournal_title
Bulletin of mathematical biologyauthors
White C,Bridge LJdoi
10.1007/s11538-017-0387-xsubject
Has Abstractpub_date
2019-09-01 00:00:00pages
3542-3574issue
9eissn
0092-8240issn
1522-9602pii
10.1007/s11538-017-0387-xjournal_volume
81pub_type
杂志文章abstract：:The origin of the modern genetic code and the mechanisms that have contributed to its present form raise many questions. The main goal of this work is to test two hypotheses concerning the development of the genetic code for their compatibility and complementarity and see if they could benefit from each other. On the ...
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