The three-dimensional structures of human parvovirus B19 VP2 capsids, alone and complexed with its cellular receptor, globoside, have been determined to 26 A resolution. The B19 capsid structure, reconstructed from cryo-electron micrographs of vitrified specimens, has depressions on the icosahedral 2-fold and 3-fold axes, as well as a canyon-like region around the 5-fold axes. Similar results had previously been found in an 8 A resolution map derived from x-ray diffraction data. Other parvoviral structures have a cylindrical channel along the 5-fold icosahedral axes, whereas density covers the 5-fold axes in B19. The glycolipid receptor molecules bind into the depressions on the 3-fold axes of the B19:globoside complex. A model of the tetrasaccharide component ofgloboside, organized as a trimeric fiber, fits well into the difference density representing the globoside receptor. Escape mutations to neutralizing antibodies map onto the capsid surface at regions immediately surrounding the globoside attachment sites. The proximity of the antigenic epitopes to the receptor site suggests that neutralization of virus infectivity is caused by preventing attachment of viruses to cells.Parvovirus B19 is the only member of Parvoviridae pathogenic to man (1, 2). Acute infection causes a childhood measles-like rash condition, erythrema infectosium, also known as fifth disease, and acute or chronic arthritis in adults. In persons with underlying hemolysis, acute B19 infection results in transient aplastic crises, due to cessation in red blood cell production, which is caused by tropism of B19 to erythroid progenitor cells. In immunocompromised individuals, such as AIDS patients and patients undergoing immunosuppressive drug therapy, persistent B19 infection causes chronic severe anemia due to erythroid marrow failure. B19 infection of pregnant women may cause hydrops fetalis (congestive heart failure) of the fetus and spontaneous abortions due to the inability of the fetus to mount an adequate immune response.Parvoviruses have a single-stranded DNA genome encapsidated in a T = 1 (60 structurally equivalent subunits) icosahedral protein capsid, approximately 260 A in diameter.The major structural protein, VP2, has a molecular mass of 58,000 and consists of an eight-stranded, anti-parallel, (3-barrel motif (with , strands B, C, . . . , I), similar to that found in many other viral capsid proteins (3). This (3-barrel structure contains only about one-third of the amino acid content in each polypeptide and lies mostly below the capsid surface, which is formed by large insertions between the /3-strands. For canine parvovirus (CPV) (4) and feline panleukopenia virus (FPV) (5), the loops between the B and C (loop 1), E and F (loop 2), and G and H (loops 3 and 4) (3-strands contain 36, 74, and 223 residues, respectively. These loops form most of the capsid surface, with loops 3 and 4 forming the bulk of the spikes that extend 22 A radially outwards around the 3-fold axes. The insertion of 20 amino acids between the D and E st...