Affimer proteins inhibit immune complex binding to FcγRIIIa with high specificity through competitive and allosteric modes of action
Protein-protein interactions are essential for the control of cellular functions and are critical for regulation of the immune system. One example is the binding of Fc regions of IgG to the Fc gamma receptors (FcγRs). High sequence identity (98%) between the genes encoding FcγRIIIa (expressed on mac...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
National Academy of Sciences
2017
|
| _version_ | 1797079185334730752 |
|---|---|
| author | Robinson, JI Baxter, EW Owen, RL Thomsen, M Tomlinson, DC Waterhouse, MP Win, SJ Nettleship, JE Tiede, C Foster, RJ Owens, RJ Fishwick, CWG Harris, SA Goldman, A McPherson, MJ Morgan, AW |
| author_facet | Robinson, JI Baxter, EW Owen, RL Thomsen, M Tomlinson, DC Waterhouse, MP Win, SJ Nettleship, JE Tiede, C Foster, RJ Owens, RJ Fishwick, CWG Harris, SA Goldman, A McPherson, MJ Morgan, AW |
| author_sort | Robinson, JI |
| collection | OXFORD |
| description | Protein-protein interactions are essential for the control of cellular functions and are critical for regulation of the immune system. One example is the binding of Fc regions of IgG to the Fc gamma receptors (FcγRs). High sequence identity (98%) between the genes encoding FcγRIIIa (expressed on macrophages and natural killer cells) and FcγRIIIb (expressed on neutrophils) has prevented the development of monospecific agents against these therapeutic targets. We now report the identification of FcγRIIIa-specific artificial binding proteins called "Affimer" that block IgG binding and abrogate FcγRIIIa-mediated downstream effector functions in macrophages, namely TNF release and phagocytosis. Cocrystal structures and molecular dynamics simulations have revealed the structural basis of this specificity for two Affimer proteins: One binds directly to the Fc binding site, whereas the other acts allosterically. |
| first_indexed | 2024-03-07T00:42:08Z |
| format | Journal article |
| id | oxford-uuid:8369166f-855a-4bce-b774-89e65267d731 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T00:42:08Z |
| publishDate | 2017 |
| publisher | National Academy of Sciences |
| record_format | dspace |
| spelling | oxford-uuid:8369166f-855a-4bce-b774-89e65267d7312022-03-26T21:44:01ZAffimer proteins inhibit immune complex binding to FcγRIIIa with high specificity through competitive and allosteric modes of actionJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:8369166f-855a-4bce-b774-89e65267d731EnglishSymplectic Elements at OxfordNational Academy of Sciences2017Robinson, JIBaxter, EWOwen, RLThomsen, MTomlinson, DCWaterhouse, MPWin, SJNettleship, JETiede, CFoster, RJOwens, RJFishwick, CWGHarris, SAGoldman, AMcPherson, MJMorgan, AWProtein-protein interactions are essential for the control of cellular functions and are critical for regulation of the immune system. One example is the binding of Fc regions of IgG to the Fc gamma receptors (FcγRs). High sequence identity (98%) between the genes encoding FcγRIIIa (expressed on macrophages and natural killer cells) and FcγRIIIb (expressed on neutrophils) has prevented the development of monospecific agents against these therapeutic targets. We now report the identification of FcγRIIIa-specific artificial binding proteins called "Affimer" that block IgG binding and abrogate FcγRIIIa-mediated downstream effector functions in macrophages, namely TNF release and phagocytosis. Cocrystal structures and molecular dynamics simulations have revealed the structural basis of this specificity for two Affimer proteins: One binds directly to the Fc binding site, whereas the other acts allosterically. |
| spellingShingle | Robinson, JI Baxter, EW Owen, RL Thomsen, M Tomlinson, DC Waterhouse, MP Win, SJ Nettleship, JE Tiede, C Foster, RJ Owens, RJ Fishwick, CWG Harris, SA Goldman, A McPherson, MJ Morgan, AW Affimer proteins inhibit immune complex binding to FcγRIIIa with high specificity through competitive and allosteric modes of action |
| title | Affimer proteins inhibit immune complex binding to FcγRIIIa with high specificity through competitive and allosteric modes of action |
| title_full | Affimer proteins inhibit immune complex binding to FcγRIIIa with high specificity through competitive and allosteric modes of action |
| title_fullStr | Affimer proteins inhibit immune complex binding to FcγRIIIa with high specificity through competitive and allosteric modes of action |
| title_full_unstemmed | Affimer proteins inhibit immune complex binding to FcγRIIIa with high specificity through competitive and allosteric modes of action |
| title_short | Affimer proteins inhibit immune complex binding to FcγRIIIa with high specificity through competitive and allosteric modes of action |
| title_sort | affimer proteins inhibit immune complex binding to fcγriiia with high specificity through competitive and allosteric modes of action |
| work_keys_str_mv | AT robinsonji affimerproteinsinhibitimmunecomplexbindingtofcgriiiawithhighspecificitythroughcompetitiveandallostericmodesofaction AT baxterew affimerproteinsinhibitimmunecomplexbindingtofcgriiiawithhighspecificitythroughcompetitiveandallostericmodesofaction AT owenrl affimerproteinsinhibitimmunecomplexbindingtofcgriiiawithhighspecificitythroughcompetitiveandallostericmodesofaction AT thomsenm affimerproteinsinhibitimmunecomplexbindingtofcgriiiawithhighspecificitythroughcompetitiveandallostericmodesofaction AT tomlinsondc affimerproteinsinhibitimmunecomplexbindingtofcgriiiawithhighspecificitythroughcompetitiveandallostericmodesofaction AT waterhousemp affimerproteinsinhibitimmunecomplexbindingtofcgriiiawithhighspecificitythroughcompetitiveandallostericmodesofaction AT winsj affimerproteinsinhibitimmunecomplexbindingtofcgriiiawithhighspecificitythroughcompetitiveandallostericmodesofaction AT nettleshipje affimerproteinsinhibitimmunecomplexbindingtofcgriiiawithhighspecificitythroughcompetitiveandallostericmodesofaction AT tiedec affimerproteinsinhibitimmunecomplexbindingtofcgriiiawithhighspecificitythroughcompetitiveandallostericmodesofaction AT fosterrj affimerproteinsinhibitimmunecomplexbindingtofcgriiiawithhighspecificitythroughcompetitiveandallostericmodesofaction AT owensrj affimerproteinsinhibitimmunecomplexbindingtofcgriiiawithhighspecificitythroughcompetitiveandallostericmodesofaction AT fishwickcwg affimerproteinsinhibitimmunecomplexbindingtofcgriiiawithhighspecificitythroughcompetitiveandallostericmodesofaction AT harrissa affimerproteinsinhibitimmunecomplexbindingtofcgriiiawithhighspecificitythroughcompetitiveandallostericmodesofaction AT goldmana affimerproteinsinhibitimmunecomplexbindingtofcgriiiawithhighspecificitythroughcompetitiveandallostericmodesofaction AT mcphersonmj affimerproteinsinhibitimmunecomplexbindingtofcgriiiawithhighspecificitythroughcompetitiveandallostericmodesofaction AT morganaw affimerproteinsinhibitimmunecomplexbindingtofcgriiiawithhighspecificitythroughcompetitiveandallostericmodesofaction |