The study presents the structural basis for the broad and potent neutralization of HIV-1 by the antibody VRC01. VRC01 binds to the CD4-binding site on the HIV-1 gp120 envelope glycoprotein, which is typically masked by glycan and conformational changes. However, VRC01 achieves neutralization by focusing on a conformationally invariant site of initial CD4 attachment, allowing it to overcome the masking that reduces the potency of most CD4-binding-site antibodies. The structure of VRC01 in complex with an HIV-1 gp120 core reveals that the heavy chain of VRC01 interacts with gp120 in a manner similar to CD4, but with a 43° rotation and a 6-Å shift, which positions VRC01 to the conformationally invariant site. This interaction is facilitated by V-gene-derived regions that have been substantially altered from their genomic precursors. The study also highlights the role of affinity maturation in VRC01's ability to neutralize HIV-1, as well as the importance of precise targeting to the CD4-binding site. The findings suggest that VRC01's unique structural features, including a high degree of affinity maturation, an extra disulfide bond, and a site for N-linked glycosylation, contribute to its effectiveness. The study also discusses the implications of these findings for vaccine design, emphasizing the importance of understanding the structural basis of antibody-antigen interactions in the development of effective HIV-1 vaccines.The study presents the structural basis for the broad and potent neutralization of HIV-1 by the antibody VRC01. VRC01 binds to the CD4-binding site on the HIV-1 gp120 envelope glycoprotein, which is typically masked by glycan and conformational changes. However, VRC01 achieves neutralization by focusing on a conformationally invariant site of initial CD4 attachment, allowing it to overcome the masking that reduces the potency of most CD4-binding-site antibodies. The structure of VRC01 in complex with an HIV-1 gp120 core reveals that the heavy chain of VRC01 interacts with gp120 in a manner similar to CD4, but with a 43° rotation and a 6-Å shift, which positions VRC01 to the conformationally invariant site. This interaction is facilitated by V-gene-derived regions that have been substantially altered from their genomic precursors. The study also highlights the role of affinity maturation in VRC01's ability to neutralize HIV-1, as well as the importance of precise targeting to the CD4-binding site. The findings suggest that VRC01's unique structural features, including a high degree of affinity maturation, an extra disulfide bond, and a site for N-linked glycosylation, contribute to its effectiveness. The study also discusses the implications of these findings for vaccine design, emphasizing the importance of understanding the structural basis of antibody-antigen interactions in the development of effective HIV-1 vaccines.