4JZZ

Crystal structure of CD4-mimetic miniprotein M48U1 in complex with HIV-1 YU2 gp120 in C2221 space group

Summary for 4JZZ

• Entry DOI: 10.2210/pdb4jzz/pdb
• Related: 4JZW 4K0A
• Related PRD ID: PRD_001094
• Descriptor: HIV-1 YU2 gp120 glycoprotein, CD4-MIMETIC MINIPROTEIN M48U1, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• Functional Keywords: hiv-1 attachment protein gp120, hiv-1 envelope, viral protein-inhibitor complex, viral protein/inhibitor
• Biological source: Human immunodeficiency virus 1; More
• Total number of polymer chains: 2
• Total formula weight: 47149.39

Authors

Acharya, P.,Kwong, P.D. (deposition date: 2013-04-03, release date: 2013-06-12, Last modification date: 2025-03-26)

Primary citation

Acharya, P.,Luongo, T.S.,Louder, M.K.,McKee, K.,Yang, Y.,Do Kwon, Y.,Mascola, J.R.,Kessler, P.,Martin, L.,Kwong, P.D.
Structural Basis for Highly Effective HIV-1 Neutralization by CD4-Mimetic Miniproteins Revealed by 1.5 A Cocrystal Structure of gp120 and M48U1.
Structure, 21:1018-1029, 2013

PubMed Abstract: The interface between the HIV-1 gp120 envelope glycoprotein and the CD4 receptor contains an unusual interfacial cavity, the "Phe43 cavity", which CD4-mimetic miniproteins with nonnatural extensions can potentially utilize to enhance their neutralization of HIV-1. Here, we report cocrystal structures of HIV-1 gp120 with miniproteins M48U1 and M48U7, which insert cyclohexylmethoxy and 5-hydroxypentylmethoxy extensions, respectively, into the Phe43 cavity. Both inserts displayed flexibility and hydrophobic interactions, but the M48U1 insert showed better shape complementarity with the Phe43 cavity than the M48U7 insert. Subtle alteration in the gp120 conformation played a substantial role in optimizing fit. With M48U1, these translated into a YU2-gp120 affinity of 0.015 nM and neutralization of all 180 circulating HIV-1 strains tested, except clade-A/E isolates with noncanonical Phe43 cavities. Ligand chemistry, shape complementarity, surface burial, and gp120 conformation act in concert to modulate binding of ligands to the gp120-Phe43 cavity and, when optimized, can effect near-pan-neutralization of HIV-1.

PubMed: 23707685
DOI: 10.1016/j.str.2013.04.015

Experimental method

X-RAY DIFFRACTION (1.49 Å)