The study investigates the structural basis for the broad and potent neutralization of HIV-1 by the antibody VRC01. VRC01 interacts with the HIV-1 gp120 envelope glycoprotein in a manner similar to the CD4 receptor, focusing on the conformationally invariant site of initial CD4 attachment. This interaction allows VRC01 to overcome the masking that diminishes the neutralization potency of most CD4-binding-site antibodies. The heavy chain of VRC01 interacts with gp120 in a way that mimics CD4, with a 43° rotation and a 6-Å shift from the CD4-defined orientation. VRC01 contacts gp120 mainly through V-gene-derived regions that have been altered from their genomic precursors. The antibody's ability to recognize both CD4-bound and non-CD4-bound conformations of gp120, along with its high affinity for both conformations, contributes to its broad neutralization capacity. The study also examines the natural resistance to VRC01 and the role of affinity maturation in enhancing its binding affinity. The findings provide insights into the structural basis of VRC01's neutralization mechanism and suggest potential strategies for eliciting similar antibodies through vaccine design.The study investigates the structural basis for the broad and potent neutralization of HIV-1 by the antibody VRC01. VRC01 interacts with the HIV-1 gp120 envelope glycoprotein in a manner similar to the CD4 receptor, focusing on the conformationally invariant site of initial CD4 attachment. This interaction allows VRC01 to overcome the masking that diminishes the neutralization potency of most CD4-binding-site antibodies. The heavy chain of VRC01 interacts with gp120 in a way that mimics CD4, with a 43° rotation and a 6-Å shift from the CD4-defined orientation. VRC01 contacts gp120 mainly through V-gene-derived regions that have been altered from their genomic precursors. The antibody's ability to recognize both CD4-bound and non-CD4-bound conformations of gp120, along with its high affinity for both conformations, contributes to its broad neutralization capacity. The study also examines the natural resistance to VRC01 and the role of affinity maturation in enhancing its binding affinity. The findings provide insights into the structural basis of VRC01's neutralization mechanism and suggest potential strategies for eliciting similar antibodies through vaccine design.