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Biophysical Analysis of Anti-Inflammatory Viral CC Chemokine Binding Protein vCCI


Viruses have evolved mechanisms to subvert the immune system by interfering with chemokine signaling. The two mechanisms of evasion discussed in this thesis are proteins which bind chemokines to prevent them binding their receptors (as vCCI does) and chemokine analogs (such as vMIP-II) that competitively inhibit chemokines. Molecular dynamics simulations suggested that Y80 in vCCI is important for propping open the acidic loop, which keeps the binding site open. We investigated this hypothesis using ITC, NMR, and CD. For vCCI WT and vCCI Y80A, results included: a higher KD for the mutant (2.99 x 10-8 M) when binding vMIP-II compared to vCCI WT (≤1.00 x 10-10 M), key residues involved in binding shifted in the unbound mutant NMR HSQC spectrum, and the mutant had lower stability demonstrated by a 6.1°C reduction in Tm. The Y80A mutation lowers chemokine affinity, which may indeed be due to collapse of the substrate-binding loop.

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