The carboxyl-terminal domain, residues 146 to 231, of the human immunodeficiency virus-1 (HIV-1) capsid protein [CA(146-231)] is required for capsid dimerization and viral assembly. This domain contains a stretch of 20 residues, called the major homology region (MHR), which is conserved across retroviruses and is essential for viral assembly, maturation, and infectivity. The crystal structures of CA(146-231) and CA(151-231) reveal that the globular domain is composed of four helices and an extended amino-terminal strand. CA(146-231) dimerizes through parallel packing of helix 2 across a dyad. The MHR is distinct from the dimer interface and instead forms an intricate hydrogen-bonding network that interconnects strand 1 and helices 1 and 2. Alignment of the CA(146-231) dimer with the crystal structure of the capsid amino-terminal domain provides a model for the intact protein and extends models for assembly of the central conical core of HIV-1.

The HIV-1 capsid protein forms the conical core structure at the center of the mature virion. Capsid also binds the human peptidyl prolyl isomerase, cyclophilin A, thereby packaging the enzyme into the virion. Cyclophilin A subsequently performs an essential function in HIV-1 replication, possibly helping to disassemble the capsid core upon infection. We report the 2.36 A crystal structure of the N-terminal domain of HIV-1 capsid (residues 1-151) in complex with human cyclophilin A. A single exposed capsid loop (residues 85-93) binds in the enzyme's active site, and Pro-90 adopts an unprecedented trans conformation. The structure suggests how cyclophilin A can act as a sequence-specific binding protein and a nonspecific prolyl isomerase. In the crystal lattice, capsid molecules assemble into continuous planar strips. Side by side association of these strips may allow capsid to form the surface of the viral core. Cyclophilin A could then function by weakening the association between capsid strips, thereby promoting disassembly of the viral core.

The three-dimensional structure of the amino-terminal core domain (residues 1 through 151) of the human immunodeficiency virus-type 1 (HIV-1) capsid protein has been solved by multidimensional heteronuclear magnetic resonance spectroscopy. The structure is unlike those of previously characterized viral coat proteins and is composed of seven alpha helices, two beta hairpins, and an exposed partially ordered loop. The domain is shaped like an arrowhead, with the beta hairpins and loop exposed at the trailing edge and the carboxyl-terminal helix projecting from the tip. The proline residue Pro1 forms a salt bridge with a conserved, buried aspartate residue (Asp51), which suggests that the amino terminus of the protein rearranges upon proteolytic maturation. The binding site for cyclophilin A, a cellular rotamase that is packaged into the HIV-1 virion, is located on the exposed loop and encompasses the essential proline residue Pro90. In the free monomeric domain, Pro90 adopts kinetically trapped cis and trans conformations, raising the possibility that cyclophilin A catalyzes interconversion of the cis- and trans-Pro90 loop structures.

The human immunodeficiency virus type I (HIV‐1) capsid protein is initially synthesized as the central domain of the Gag polyprotein, and is subsequently proteolytically processed into a discrete 231‐amino‐acid protein that forms the distinctive conical core of the mature virus. The crystal structures of two proteins that span the C‐terminal domain of the capsid are reported here: one encompassing residues 146–231 (CA146–231) and the other extending to include the 14‐residue p2 domain of Gag (CA146–p2). The isomorphous CA146–231 and CA146–­p2 structures were determined by molecular replacement and have been refined at 2.6 Å resolution to R factors of 22.3 and 20.7% (Rfree = 28.1 and 27.5%), respectively. The ordered domains comprise residues 148–219 for CA146–231 and 148–218 for CA146–p2, and their refined structures are essentially identical. The proteins are composed of a 310 helix followed by an extended strand and four α‐helices. A crystallographic twofold generates a dimer that is stabilized by parallel packing of an α‐­helix 2 across the dimer interface and by packing of the 310 helix into a groove created by α‐­helices 2 and 3 of the partner molecule. CA146–231 and CA146–p2 dimerize with the full affinity of the intact capsid protein, and their structures therefore reveal the essential dimer interface of the HIV‐1 capsid.

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