Structural analysis of nested neutralizing and non-neutralizing B cell epitopes on ricin toxin's enzymatic subunit

Rudolph, Michael J.; Vance, David J.; Cassidy, Michael S.; Rong, Yinghui; Shoemaker, Charles B.; Mantis, Nicholas J.

doi:10.1002/prot.25062

Structural analysis of nested neutralizing and non-neutralizing B cell epitopes on ricin toxin's enzymatic subunit

Journal Article · Mon May 09 00:00:00 EDT 2016 · Proteins

DOI:https://doi.org/10.1002/prot.25062· OSTI ID:1267468

Rudolph, Michael J. ^[1]; Vance, David J. ^[2]; Cassidy, Michael S. ^[1]; Rong, Yinghui ^[2]; Shoemaker, Charles B. ^[3]; Mantis, Nicholas J. ^[4]

New York Structural Biology Center, New York, NY (United States)
New York State Dept. of Health, Albany, NY (United States)
Tufts Cummings School of Veterinary Medicine, North Grafton, MA (United States)
New York State Dept. of Health, Albany, NY (United States); Univ. at Albany, Albany, NY (United States)

In this report, we describe the X–ray crystal structures of two single domain camelid antibodies (V_HH), F5 and F8, each in complex with ricin toxin's enzymatic subunit (RTA). F5 has potent toxin–neutralizing activity, while F8 has weak neutralizing activity. F5 buried a total of 1760 Å² in complex with RTA and made contact with three prominent secondary structural elements: α–helix B (Residues 98–106), β–strand h (Residues 113–117), and the C–terminus of α–helix D (Residues 154–156). F8 buried 1103 Å² in complex with RTA that was centered primarily on β–strand h. As such, the structural epitope of F8 is essentially nested within that of F5. All three of the F5 complementarity determining regions CDRs were involved in RTA contact, whereas F8 interactions were almost entirely mediated by CDR3, which essentially formed a seventh β–strand within RTA's centrally located β–sheet. A comparison of the two structures reported here to several previously reported (RTA–VHH) structures identifies putative contact sites on RTA, particularly α–helix B, associated with potent toxin–neutralizing activity. Here, this information has implications for rational design of RTA–based subunit vaccines for biodefense.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Inst. of Allergy and Infectious Diseases

Grant/Contract Number:: AC02-98CH10886

OSTI ID:: 1267468

Journal Information:: Proteins, Journal Name: Proteins Journal Issue: 8 Vol. 84; ISSN 0887-3585

Publisher:: WileyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Structural analysis of nested neutralizing and non-neutralizing B cell epitopes on ricin toxin's enzymatic subunit

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