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Structural basis for HCMV Pentamer recognition by neuropilin 2 and neutralizing antibodies

Journal Article · · Science Advances
 [1];  [2];  [2];  [2];  [1];  [1];  [1];  [3];  [3];  [3];  [2];  [4];  [4];  [3];  [2];  [2];  [2];  [1]
  1. Univ. of Texas, Austin, TX (United States)
  2. University of Texas Health Science Center, Houston, TX (United States)
  3. Merck & Co. Inc., Kenilworth, NJ (United States)
  4. Rutgers New Jersey Medical School, Newark, NJ (United States)
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.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1856359
Journal Information:
Science Advances, Journal Name: Science Advances Journal Issue: 10 Vol. 8; ISSN 2375-2548
Publisher:
AAASCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

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