STRUCTURES OF AN HIV AND MHC BINDING FRAGMENT FROM HUMAN CD4 AS REFINED IN 2 CRYSTAL LATTICES

Background: The T-cell surface glycoprotein CD4 interacts with class I I molecules of the major histocompatibility complex (MHC) enhancing th e signal for T-cell activation. Human CD4 also interacts, at high affi nity, with the HIV envelope glycoprotein, gp120, to mediate T-cell inf ection by HN. Crystal structures of amino-terminal two-domain (D1D2) f ragments of human CD4, which contain the residues implicated in HIV an d MHC interactions, have been reported earlier. Results: We have deter mined the crystal structure of a new D1D2 construct by molecular repla cement from a previously described crystal structure of D1D2. This str ucture has more uniform lattice contacts than are in the first. This g ives an improved image of domain D2, which in turn has permitted furth er refinement of the initial structure at 2.3 Angstrom resolution agai nst a more complete data set. The structure of the second crystal form was also refined at 2.9 Angstrom resolution. In both models, all resi dues from 1 to 178 are now well defined, including the loop regions in D2. Conclusions: Similarities of the molecular structure in the two l attices suggest that the D1D2 fragment works as a unit, with segmental flexibility largely restricted to the junction between domains D2 and D3. Variability of conformation in loops, including those implicated in MHC and HIV binding, requires an 'induced fit' in these interaction s. Well defined density for the exposed side chain of Phe43 in both cr ystals confirms a prominent role for this residue in gp120 binding.