3pp4 | pdb_00003pp4
Epitope characterization and crystal structure of GA101 provide insights into the molecular basis for the type I / type II distinction of anti- CD20 antibodies
Structural highlights
Disease[CD20_HUMAN] Defects in MS4A1 are the cause of immunodeficiency common variable type 5 (CVID5) [MIM:613495]; also called antibody deficiency due to CD20 defect. CVID5 is a primary immunodeficiency characterized by antibody deficiency, hypogammaglobulinemia, recurrent bacterial infections and an inability to mount an antibody response to antigen. The defect results from a failure of B-cell differentiation and impaired secretion of immunoglobulins; the numbers of circulating B-cells is usually in the normal range, but can be low.[1] Function[CD20_HUMAN] This protein may be involved in the regulation of B-cell activation and proliferation. Publication Abstract from PubMedCD20 is a cell surface marker of normal and malignant B cells. Rituximab, a monoclonal antibody targeting CD20, has improved treatment of malignant lymphomas. Therapeutic CD20 antibodies are classified as either type I or II based on different mechanisms of killing malignant B-cells. To reveal the molecular basis of this distinction, we fine mapped the epitopes recognized by both types. We also determined the first X-ray structure of a type II antibody by crystallizing the obinutuzumab (GA101) Fab fragment alone and in complex with a CD20 cyclopeptide. Despite recognizing an overlapping epitope, GA101 binds CD20 in a completely different orientation than type I antibodies. Moreover, the elbow angle of GA101 is almost 30 degrees wider than in type I antibodies potentially resulting in different spatial arrangements of two CD20 molecules bound to a single GA101 or rituximab molecule. By protein tomography different CD20 complexes were found associated with the two antibodies and confocal microscopy showed different membrane compartmentalization of these subpopulations of the cellular CD20 pool. Taken together, our findings offer a possible molecular explanation for the different cellular responses elicited by type I and II antibodies. Epitope characterization and crystal structure of GA101 provide insights into the molecular basis for type I/II distinction of CD20 antibodies.,Niederfellner G, Lammens A, Mundigl O, Georges GJ, Schaefer W, Schwaiger M, Franke A, Wiechmann K, Jenewein S, Slootstra JW, Timmerman P, Brannstrom A, Lindstrom F, Mossner E, Umana P, Hopfner KP, Klein C Blood. 2011 Mar 28. PMID:21444918[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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