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Structure paper

TitleStructural basis for HCMV Pentamer recognition by neuropilin 2 and neutralizing antibodies.
Journal, issue, pagesSci Adv, Vol. 8, Issue 10, Page eabm2546, Year 2022
Publish dateMar 11, 2022
AuthorsDaniel Wrapp / Xiaohua Ye / Zhiqiang Ku / Hang Su / Harrison G Jones / Nianshuang Wang / Akaash K Mishra / Daniel C Freed / Fengsheng Li / Aimin Tang / Leike Li / Dabbu Kumar Jaijyan / Hua Zhu / Dai Wang / Tong-Ming Fu / Ningyan Zhang / Zhiqiang An / Jason S McLellan /
PubMed AbstractHuman cytomegalovirus (HCMV) encodes multiple surface glycoprotein complexes to infect a variety of cell types. The HCMV Pentamer, composed of gH, gL, UL128, UL130, and UL131A, enhances entry into ...Human cytomegalovirus (HCMV) encodes multiple surface glycoprotein complexes to infect a variety of cell types. The HCMV Pentamer, composed of gH, gL, UL128, UL130, and UL131A, enhances entry into epithelial, endothelial, and myeloid cells by interacting with the cell surface receptor neuropilin 2 (NRP2). Despite the critical nature of this interaction, the molecular determinants that govern NRP2 recognition remain unclear. Here, we describe the cryo-EM structure of NRP2 bound to Pentamer. The high-affinity interaction between these proteins is calcium dependent and differs from the canonical carboxyl-terminal arginine (CendR) binding that NRP2 typically uses. We also determine the structures of four neutralizing human antibodies bound to the HCMV Pentamer to define susceptible epitopes. Two of these antibodies compete with NRP2 binding, but the two most potent antibodies recognize a previously unidentified epitope that does not overlap the NRP2-binding site. Collectively, these findings provide a structural basis for HCMV tropism and antibody-mediated neutralization.
External linksSci Adv / PubMed:35275718 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution1.9 - 4.02 Å
Structure data

22788

7kbb

EMDB-22788, PDB-7kbb:
Cryo-EM structure of the HCMV pentamer bound by Fabs 2-18 and 8I21
Method: EM (single particle) / Resolution: 4.02 Å

23629

7m22

EMDB-23629, PDB-7m22:
Cryo-EM structure of the HCMV pentamer bound by human neuropilin 2
Method: EM (single particle) / Resolution: 3.65 Å

23640

7m30

EMDB-23640, PDB-7m30:
Cryo-EM structure of the HCMV pentamer bound by antibodies 1-103, 1-32 and 2-25
Method: EM (single particle) / Resolution: 3.81 Å

PDB-7kba:
Crystal structure of the HCMV pentamer-specific Fab 2-18
Method: X-RAY DIFFRACTION / Resolution: 2.8 Å

PDB-7lyv:
Crystal structure of the HCMV pentamer-specific antibody 1-103
Method: X-RAY DIFFRACTION / Resolution: 1.9 Å

PDB-7lyw:
Crystal structure of the HCMV pentamer-specific antibody 2-25
Method: X-RAY DIFFRACTION / Resolution: 2.51 Å

PDB-7m1c:
Crystal structure of the HCMV pentamer-specific antibody 1-32
Method: X-RAY DIFFRACTION / Resolution: 2.1 Å

Chemicals

ChemComp-HOH:
WATER / Water

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-CA:
Unknown entry

Source
  • Human betaherpesvirus 5
  • homo sapiens (human)
  • human cytomegalovirus
KeywordsANTIVIRAL PROTEIN / IMMUNE SYSTEM / Antibody / HCMV / Fab / VIRAL PROTEIN/IMMUNE SYSTEM / HCMV pentamer / complex / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex / cytomegalovirus / VIRAL PROTEIN/HOST RECEPTOR / NRP2 / host receptor / VIRAL PROTEIN-HOST RECEPTOR complex / immunocomplex

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