Integrin receptor GPIIb/IIIa bound state conformation of the fibrinogen gamma-chain C-terminal peptide 400-411: NMR and transfer NOE studies.
The C-terminal dodecapeptide from human fibrinogen gamma-chain, residues 400-411, HHLG-GAKQAGDV (gamma12), is known to inhibit fibrinogen-mediated platelet cell aggregation via competitive interactions with platelet glycoprotein integrin receptor GPIIb/IIIa. NMR studies of gamma12 in the presence of purified GPIIb/IIIa (230 kDa) demonstrate that two gamma12 binding states (gamma12-I and gamma12-II) are present on the integrin receptor. The N-terminal sequence HHLG is crucial to formation of gamma12 state I since in a shorter gamma-chain octapeptide, GAKQAGDV, gamma12-I is not observed. Addition of the hexapeptide GRGDSP to the gamma12-receptor preparation effectively removes the gamma12-I population, suggesting either that gamma12 and GRGDSP share one binding site or that their binding sites are allosterically linked. Distance geometry calculations using transfer NOEs from gamma12-I (gamma12-II shows practically no NOEs) indicate the presence of helix conformation when bound to the receptor. Line broadening and chemical shift changes relative to free gamma12 suggest that gamma12 interacts with GPIIb/IIIa primarily through N-terminal residues H400 to Q407.
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Department of Biochemistry, Biomedical Engineering Center, University of Minnesota, Minneapolis, 55455, USA.
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D000595:Amino Acid Sequence; D001665:Binding Sites; D005340:Fibrinogen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation
D008024:Ligands; D009842:Oligopeptides; D010446:Peptide Fragments; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C047981:arginyl-glycyl-aspartic acid; D005340:Fibrinogen