Title:Interaction of Chemokines with their Receptors - From Initial Chemokine Binding to Receptor Activating Steps
Volume: 21
Issue: 31
Author(s): Stefanie Thiele and Mette Marie Rosenkilde
Affiliation:
关键词:
7TM受体，趋化因子，G蛋白耦联受体（GPCR），配体受体相互作用，突变，正性结合位点，结构，两步机制。
摘要: The human chemokine system comprises 19 seven-transmembrane helix (7TM) receptors and 45 endogenous
chemokines that often interact with each other in a promiscuous manner. Due to the chemokine system’s primary function
in leukocyte migration, it has a central role in immune homeostasis and surveillance. Chemokines are a group of 8-12 kDa
large peptides with a secondary structure consisting of a flexible N-terminus and a core-domain usually stabilized by two
conserved disulfide bridges. They mainly interact with the extracellular domains of their cognate 7TM receptors. Affinityand
activity-contributing interactions are attributed to different domains and known to occur in two steps. Here,
knowledge on chemokine and receptor domains involved in the first binding-step and the second activation-step is reviewed.
A mechanism comprising at least two steps seems consistent; however, several intermediate interactions possibly
occur, resulting in a multi-step process, as recently proposed for other 7TM receptors. Overall, the N-terminus of chemokine
receptors is pivotal for binding of all chemokines. During receptor activation, differences between the two major
chemokine subgroups occur, as CC-chemokines mainly interact with or rely on transmembrane receptor residues, while
CXC-chemokines use residues located further exterior. Moreover, different chemokines for the same receptor often bind
at different sites, uncovering the existence of several orthosteric sites thereby adding another level of complexity. This
gives rise to a probe-dependency of small molecule “drug-like” ligands, which, depending on the chemokine interaction,
may bind allosteric for some, and orthosteric for other chemokines targeting the same receptor, thereby resulting in probedependent
pharmacodynamics.
