ジャーナル: EMBO Mol Med / 年: 2014 タイトル: A potent anti-dengue human antibody preferentially recognizes the conformation of E protein monomers assembled on the virus surface. 著者: Guntur Fibriansah / Joanne L Tan / Scott A Smith / Adamberage R de Alwis / Thiam-Seng Ng / Victor A Kostyuchenko / Kristie D Ibarra / Jiaqi Wang / Eva Harris / Aravinda de Silva / James E Crowe / Shee-Mei Lok / 要旨: Dengue virus (DENV), which consists of four serotypes (DENV1-4), infects over 400 million people annually. Previous studies have indicated most human monoclonal antibodies (HMAbs) from dengue ...Dengue virus (DENV), which consists of four serotypes (DENV1-4), infects over 400 million people annually. Previous studies have indicated most human monoclonal antibodies (HMAbs) from dengue patients are cross-reactive and poorly neutralizing. Rare neutralizing HMAbs are usually serotype-specific and bind to quaternary structure-dependent epitopes. We determined the structure of DENV1 complexed with Fab fragments of a highly potent HMAb 1F4 to 6 Å resolution by cryo-EM. Although HMAb 1F4 appeared to bind to virus and not E proteins in ELISAs in the previous study, our structure showed that the epitope is located within an envelope (E) protein monomer, and not across neighboring E proteins. The Fab molecules bind to domain I (DI), and DI-DII hinge of the E protein. We also showed that HMAb 1F4 can neutralize DENV at different stages of viral entry in a cell type and receptor dependent manner. The structure reveals the mechanism by which this potent and specific antibody blocks viral infection.
A: ENVELOPE PROTEIN B: POLYPROTEIN C: ENVELOPE PROTEIN D: POLYPROTEIN E: ENVELOPE PROTEIN F: POLYPROTEIN H: HEAVY CHAIN FAB FRAGMENT OF ANTIBODY 1F4 L: LIGHT CHAIN FAB FRAGMENT OF ANTIBODY 1F4 M: HEAVY CHAIN FAB FRAGMENT OF ANTIBODY 1F4 N: LIGHT CHAIN FAB FRAGMENT OF ANTIBODY 1F4 ヘテロ分子
A: ENVELOPE PROTEIN B: POLYPROTEIN C: ENVELOPE PROTEIN D: POLYPROTEIN E: ENVELOPE PROTEIN F: POLYPROTEIN H: HEAVY CHAIN FAB FRAGMENT OF ANTIBODY 1F4 L: LIGHT CHAIN FAB FRAGMENT OF ANTIBODY 1F4 M: HEAVY CHAIN FAB FRAGMENT OF ANTIBODY 1F4 N: LIGHT CHAIN FAB FRAGMENT OF ANTIBODY 1F4 ヘテロ分子
A: ENVELOPE PROTEIN B: POLYPROTEIN C: ENVELOPE PROTEIN D: POLYPROTEIN E: ENVELOPE PROTEIN F: POLYPROTEIN H: HEAVY CHAIN FAB FRAGMENT OF ANTIBODY 1F4 L: LIGHT CHAIN FAB FRAGMENT OF ANTIBODY 1F4 M: HEAVY CHAIN FAB FRAGMENT OF ANTIBODY 1F4 N: LIGHT CHAIN FAB FRAGMENT OF ANTIBODY 1F4 ヘテロ分子
x 5
icosahedral pentamer
1.45 MDa, 50 ポリマー
分子量 (理論値)
分子数
合計 (水以外)
1,446,437
80
ポリマ-
1,432,689
50
非ポリマー
13,748
30
水
0
タイプ
名称
対称操作
数
identity operation
1_555
x,y,z
1
point symmetry operation
4
4
A: ENVELOPE PROTEIN B: POLYPROTEIN C: ENVELOPE PROTEIN D: POLYPROTEIN E: ENVELOPE PROTEIN F: POLYPROTEIN H: HEAVY CHAIN FAB FRAGMENT OF ANTIBODY 1F4 L: LIGHT CHAIN FAB FRAGMENT OF ANTIBODY 1F4 M: HEAVY CHAIN FAB FRAGMENT OF ANTIBODY 1F4 N: LIGHT CHAIN FAB FRAGMENT OF ANTIBODY 1F4 ヘテロ分子