4B50

Crystal structure of the HIV-1 gp41 MPER-specific llama VHH 2H10

Summary for 4B50

• Entry DOI: 10.2210/pdb4b50/pdb
• Descriptor: 2H10 LLAMA VHH (2 entities in total)
• Functional Keywords: immune system, neutralizing antibody
• Biological source: LAMA GLAMA (LLAMA)
• Total number of polymer chains: 1
• Total formula weight: 13351.95

Authors

Lutje Hulsik, D.,Sabin, C.,Macheboeuf, P.,Weissenhorn, W. (deposition date: 2012-08-02, release date: 2013-03-27, Last modification date: 2024-11-13)

Primary citation

Lutje Hulsik, D.,Liu, Y.Y.,Strokappe, N.M.,Battella, S.,El Khattabi, M.,Mccoy, L.E.,Sabin, C.,Hinz, A.,Hock, M.,Macheboeuf, P.,Bonvin, A.M.,Langedijk, J.P.,Davis, D.,Forsman Quigley, A.,Aasa-Chapman, M.M.,Seaman, M.S.,Ramos, A.,Poignard, P.,Favier, A.,Simorre, J.P.,Weiss, R.A.,Verrips, C.T.,Weissenhorn, W.,Rutten, L.
A Gp41 Mper-Specific Llama Vhh Requires a Hydrophobic Cdr3 for Neutralization But not for Antigen Recognition.
Plos Pathog., 9:3202-, 2013

PubMed Abstract: The membrane proximal external region (MPER) of the HIV-1 glycoprotein gp41 is targeted by the broadly neutralizing antibodies 2F5 and 4E10. To date, no immunization regimen in animals or humans has produced HIV-1 neutralizing MPER-specific antibodies. We immunized llamas with gp41-MPER proteoliposomes and selected a MPER-specific single chain antibody (VHH), 2H10, whose epitope overlaps with that of mAb 2F5. Bi-2H10, a bivalent form of 2H10, which displayed an approximately 20-fold increased affinity compared to the monovalent 2H10, neutralized various sensitive and resistant HIV-1 strains, as well as SHIV strains in TZM-bl cells. X-ray and NMR analyses combined with mutagenesis and modeling revealed that 2H10 recognizes its gp41 epitope in a helical conformation. Notably, tryptophan 100 at the tip of the long CDR3 is not required for gp41 interaction but essential for neutralization. Thus bi-2H10 is an anti-MPER antibody generated by immunization that requires hydrophobic CDR3 determinants in addition to epitope recognition for neutralization similar to the mode of neutralization employed by mAbs 2F5 and 4E10.

PubMed: 23505368
DOI: 10.1371/JOURNAL.PPAT.1003202

Experimental method

X-RAY DIFFRACTION (1.3 Å)