Crystal structure of alpha1-antichymotrypsin variant dbs-i-allo1: an allosterically triggered drug-binding serpin for doxycycline
Structure:
Alpha-1-antichymotrypsin. Chain: a. Synonym: act,cell growth-inhibiting gene 24/25 protein,serpin a3. Engineered: yes. Mutation: yes. Other_details: all residues that are present in the sample sequence but not in the PDB file could not be modelled due to missing electron density. Alpha-1-antichymotrypsin.
K.Schmidt
et al.
(2018).
Design of an allosterically modulated doxycycline and doxorubicin drug-binding protein.
Proc Natl Acad Sci U S A,
115,
5744-5749.
PubMed id: 29760101
DOI: 10.1073/pnas.1716666115
The allosteric interplay between distant functional sites present in a single
protein provides for one of the most important regulatory mechanisms in
biological systems. While the design of ligand-binding sites into proteins
remains challenging, this holds even truer for the coupling of a newly
engineered binding site to an allosteric mechanism that regulates the ligand
affinity. Here it is shown how computational design algorithms enabled the
introduction of doxycycline- and doxorubicin-binding sites into the serine
proteinase inhibitor (serpin) family member α1-antichymotrypsin. Further
engineering allowed exploitation of the proteinase-triggered serpin-typical
S-to-R transition to modulate the ligand affinities. These design variants
follow strategies observed in naturally occurring plasma globulins that allow
for the targeted delivery of hormones in the blood. By analogy, we propose that
the variants described in the present study could be further developed to allow
for the delivery of the antibiotic doxycycline and the anticancer compound
doxorubicin to tissues/locations that express specific proteinases, such as
bacterial infection sites or tumor cells secreting matrix metalloproteinases.
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