4KA2

Crystal structure of CD4-mimetic miniprotein M48U12 in complex with HIV-1 YU2 gp120

Summary for 4KA2

• Entry DOI: 10.2210/pdb4ka2/pdb
• Related: 2I5Y 2I60 4JZW 4JZZ 4K0A
• Related PRD ID: PRD_001102
• Descriptor: HIV-1 YU2 gp120, M48U12, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: viral protein-peptide complex, hiv-1, gp120, yu2, cd4 mimic, m48u12, viral protein-inhibitor complex, viral protein/inhibitor
• Biological source: Human immunodeficiency virus 1; More
• Total number of polymer chains: 2
• Total formula weight: 46520.89

Authors

Acharya, P.,Kwong, P.D. (deposition date: 2013-04-21, release date: 2013-06-19, Last modification date: 2023-11-15)

Primary citation

Morellato-Castillo, L.,Acharya, P.,Combes, O.,Michiels, J.,Descours, A.,Ramos, O.H.,Yang, Y.,Vanham, G.,Arien, K.K.,Kwong, P.D.,Martin, L.,Kessler, P.
Interfacial Cavity Filling To Optimize CD4-Mimetic Miniprotein Interactions with HIV-1 Surface Glycoprotein.
J.Med.Chem., 56:5033-5047, 2013

PubMed Abstract: Ligand affinities can be optimized by interfacial cavity filling. A hollow (Phe43 cavity) between HIV-1 surface glycoprotein (gp120) and cluster of differentiation 4 (CD4) receptor extends beyond residue phenylalanine 43 of CD4 and cannot be fully accessed by natural amino acids. To increase HIV-1 gp120 affinity for a family of CD4-mimetic miniproteins (miniCD4s), we targeted the gp120 Phe43 cavity with 11 non-natural phenylalanine derivatives, introduced into a miniCD4 named M48 (1). The best derivative, named M48U12 (13), bound HIV-1 YU2 gp120 with 8 pM affinity and showed potent HIV-1 neutralization. It contained a methylcyclohexyl derivative of 4-aminophenylalanine, and its cocrystal structure with gp120 revealed the cyclohexane ring buried within the gp120 hydrophobic core but able to assume multiple orientations in the binding pocket, and the aniline nitrogen potentially providing a focus for further improvement. Altogether, the results provide a framework for filling the interfacial Phe43 cavity to enhance miniCD4 affinity.

PubMed: 23710622
DOI: 10.1021/jm4002988

Experimental method

X-RAY DIFFRACTION (1.79 Å)