title: CD80 binding polyproline helical peptide inhibits T cell activation.
abstract: The critical role played by the CD28/CD152-CD80/CD86 costimulatory molecules in mediating T cell activation and suppression provides attractive targets for therapeutic strategies. CD28 and CD152 share a conserved polyproline motif in the ligand-binding region. Similar proline-rich regions in globular domains preferentially adopt a polyproline type II (PP) helical conformation and are involved in transient (II)protein-protein interactions. Interestingly, in the human CD80-CD152 complex, Pro(102) of CD152 restricts the preceding proline to PP(II) helix in the binding orientation in relation to the shallow binding pocket of CD80. Peptide agents derived from binding sites of receptors that mimic the bioactive conformation have been shown to block receptor-ligand interactions. Contact preferences of the interface amino acids at the protein-protein interaction sites and the propensity of each residue to form PP(II) helix were integrated in the design of novel peptide agents referred to as CD80 competitive antagonist peptides. Structural and functional studies suggest potential therapeutic value for select CD80 competitive antagonist peptides.
authors.affiliation: Department of Oral Pathology, School of Dentistry, 1121 W. Michigan St., Indianapolis 46202, USA. mysriniv@iupui.edu
authors.forename: Mythily
authors.initials: M
authors.lastname: Srinivasan
authors.forename: Debao
authors.initials: D
authors.lastname: Lu
authors.forename: Rajaraman
authors.initials: R
authors.lastname: Eri
authors.forename: David D
authors.initials: DD
authors.lastname: Brand
authors.forename: Azizul
authors.initials: A
authors.lastname: Haque
authors.forename: Janice S
authors.initials: JS
authors.lastname: Blum
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000737:chemistry; D000943:Antigens, Differentiation / Q000737:chemistry; D001169:Arthritis, Experimental; D018122:B7-1 Antigen / Q000737:chemistry* / Q000378:metabolism; D051940:B7-2 Antigen; D001667:Binding, Competitive; D018106:CD28 Antigens / Q000737:chemistry; D060908:CTLA-4 Antigen; D049109:Cell Proliferation; D002942:Circular Dichroism; D003094:Collagen / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008024:Ligands; D008198:Lymph Nodes / Q000473:pathology; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry*; D011392:Proline / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000378:metabolism*; D013997:Time Factors
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; C497964:CD86 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C497965:Cd86 protein, mouse; C556707:Ctla4 protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; D010455:Peptides; C011083:polyproline; D003094:Collagen; D011392:Proline