Dataset Information

Molecular Recognition between A?-Specific Single-Domain Antibody and A? Misfolded Aggregates.

ABSTRACT: A? is the toxic amyloid polypeptide responsible for Alzheimer's disease (AD). Prevention and elimination of the A? misfolded aggregates are the promising therapeutic strategies for the AD treatments. Gammabody, the A?-Specific Single-domain (VH) antibody, recognizes A? aggregates with high affinity and specificity and reduces their toxicities. Employing the molecular dynamics simulations, we studied diverse gammabody-A? recognition complexes to get insights into their structural and dynamic properties and gammabody-A? recognitions. Among many heterogeneous binding modes, we focused on two gammabody-A? recognition scenarios: recognition through A? ?-sheet backbone and on sidechain surface. We found that the gammabody primarily uses the complementarity-determining region 3 (CDR3) loop with the grafted A? sequence to interact with the A? fibril, while CDR1/CDR2 loops have very little contact. The gammabody-A? complexes with backbone binding mode are more stable, explaining the gammabody's specificity towards the C-terminal A? sequence.

SUBMITTER: Zhang M

PROVIDER: S-EPMC6640678 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Publications

Molecular Recognition between Aβ-Specific Single-Domain Antibody and Aβ Misfolded Aggregates.

Zhang Mingzhen M Zheng Jie J Nussinov Ruth R Ma Buyong B

Antibodies (Basel, Switzerland) 20180713 3

Aβ is the toxic amyloid polypeptide responsible for Alzheimer's disease (AD). Prevention and elimination of the Aβ misfolded aggregates are the promising therapeutic strategies for the AD treatments. Gammabody, the Aβ-Specific Single-domain (VH) antibody, recognizes Aβ aggregates with high affinity and specificity and reduces their toxicities. Employing the molecular dynamics simulations, we studied diverse gammabody-Aβ recognition complexes to get insights into their structural and dynamic prop ...[more]

PMID: 31544877

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Project description:Alpaca-derived single-domain antibody fragments (VHHs) that target the influenza A virus nucleoprotein (NP) can protect cells from infection when expressed in the cytosol. We found that one such VHH, ?NP-VHH1, exhibits antiviral activity similar to that of Mx proteins by blocking nuclear import of incoming viral ribonucleoproteins (vRNPs) and viral transcription and replication in the nucleus. We determined a 3.2-Å crystal structure of ?NP-VHH1 in complex with influenza A virus NP. The VHH binds to a nonconserved region on the body domain of NP, which has been associated with binding to host factors and serves as a determinant of host range. Several of the NP/VHH interface residues determine sensitivity of NP to antiviral Mx GTPases. The structure of the NP/?NP-VHH1 complex affords a plausible explanation for the inhibitory properties of the VHH and suggests a rationale for the antiviral properties of Mx proteins. Such knowledge can be leveraged for much-needed novel antiviral strategies.ImportanceInfluenza virus strains can rapidly escape from protection afforded by seasonal vaccines or acquire resistance to available drugs. Additional ways to interfere with the virus life cycle are therefore urgently needed. The influenza virus nucleoprotein is one promising target for antiviral interventions. We have previously isolated alpaca-derived single-domain antibody fragments (VHHs) that protect cells from influenza virus infection if expressed intracellularly. We show here that one such VHH exhibits antiviral activities similar to those of proteins of the cellular antiviral defense (Mx proteins). We determined the three-dimensional structure of this VHH in complex with the influenza virus nucleoprotein and identified the interaction site, which overlaps regions that determine sensitivity of the virus to Mx proteins. Our data define a new vulnerability of influenza virus, help us to better understand the cellular antiviral mechanisms, and provide a well-characterized tool to further study them.

Dataset Information

Molecular Recognition between A?-Specific Single-Domain Antibody and A? Misfolded Aggregates.

Publications

Molecular Recognition between Aβ-Specific Single-Domain Antibody and Aβ Misfolded Aggregates.

Similar Datasets

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