title: Therapeutic antagonists and the conformational regulation of the beta2 integrins.
abstract: The beta2 integrins are validated therapeutic targets for inflammatory disorders. Two distinct mechanistic classes of small molecule inhibitors, termed alpha I allosteric and alpha/beta I-like allosteric antagonist, have recently been developed. The alpha I allosteric antagonists bind underneath the C-terminal helix of the I domain and stabilize the I domain in the inactive closed conformation. By contrast, the alpha/beta I-like allosteric antagonists bind to the beta2 I-like domain MIDAS and disrupt conformational signal transmission between the I and the I-like domain, leaving the I domain in a default inactive form. Furthermore, the two classes of the antagonists have opposite effects on integrin conformation; the alpha I allosteric antagonists stabilize the bent conformation, whereas the alpha/beta I-like allosteric antagonists induce the extended conformation with inactive I domain. The small molecule antagonists to the beta2 integrin highlight the importance of the structural linkages within and between integrin domains for transmission of the conformational signals and regulation of the overall conformation.
authors.affiliation: The CBR Institute for Biomedical Research, Department of Anesthesia and Pathology, Harvard Medical School, 200 Longwood, Boston, MA 02115, USA.
authors.forename: Motomu
authors.initials: M
authors.lastname: Shimaoka
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Springer
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D018821:CD18 Antigens / Q000737:chemistry / Q000187:drug effects*; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D011487:Protein Conformation / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D018821:CD18 Antigens; D006571:Heterocyclic Compounds