PDBsum entry 5om6

Transport protein

PDB id: 5om6

Contents

Protein chains

339 a.a.

39 a.a.

Ligands

CIT ×2

EDO ×2

Metals

_CL

Waters ×374

PDB id:

5om6

Name:

Transport protein

Title:

Crystal structure of alpha1-antichymotrypsin variant dbs-i-allo2: a mmp9-cleavable drug-binding serpin for doxycycline

Structure:

Alpha-1-antichymotrypsin. Chain: a, c. Fragment: unp residues 36-383. Synonym: act,cell growth-inhibiting gene 24/25 protein,serpin a3. Engineered: yes. Mutation: yes. Other_details: n-terminal residues that are present in the sample sequence but not in the PDB file could not be modelled due to missing electron density. C-terminal residues (ita...Kqa) are in chain i and

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: serpina3, aact, gig24, gig25. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Expression_system_variant: star. Expression_system_variant: star

Resolution:

1.85Å R-factor: 0.195 R-free: 0.238

Authors:

K.Schmidt,Y.A.Muller

Key ref:

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

Date:

28-Jul-17 Release date: 23-May-18

Protein chains

P01011  (AACT_HUMAN) -  Alpha-1-antichymotrypsin from Homo sapiens

Seq: 423 a.a.

Struc: 339 a.a.*

Protein chains

P01011  (AACT_HUMAN) -  Alpha-1-antichymotrypsin from Homo sapiens

Seq: 423 a.a.

Struc: 39 a.a.*

* PDB and UniProt seqs differ at 24 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains A, B, C, D: E.C.?

DOI no: 10.1073/pnas.1716666115

Proc Natl Acad Sci U S A 115:5744-5749 (2018)

PubMed id: 29760101

Design of an allosterically modulated doxycycline and doxorubicin drug-binding protein.

K.Schmidt, B.R.Gardill, A.Kern, P.Kirchweger, M.Börsch, Y.A.Muller.

ABSTRACT

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.