Refinement and Analysis of the Structure of the First Two Domains of Human CD4

Abstract

The structure of a fragment of human CD4 containing two immunoglobulin (Ig)-like domains has been determined by X-ray crystallography and refined at 2·2 Å resolution. The structure determination involved iterative building and simulated-annealing refinement, beginning with a partial model. Comparison of domain 1 with an Ig variable domain shows that CD4 has a long and prominent CDR2-like loop (the C′C″ corner) and shortened CC′ and FG loops (which mediate dimerization in IgV modules). Comparison of domain 2 with Ig modules and domain 1 shows that it can be described as a truncated Ig V domain, in which strands C″ and D are deleted. The intersheet disulfide in domain 2 is absent, and there is an altered packing of the two β-sheets together with a remodeling of the hydrophobic core. The interface between domains 1 and 2 is a lap joint with an extensive hydrophobic surface. The key features of domain 1 that contribute to the interface are found at corresponding positions in domain 2, leading us to propose that the contact between domains 2 and 3 will resemble the one between domains 1 and 2.