PDBsum entry 6bvh

Hydrolase/inhibitor

PDB id: 6bvh

Contents

Protein chains

223 a.a.

14 a.a.

Ligands

GOL ×4

SO4 ×3

Metals

_CA

Waters ×360

PDB id:

6bvh

Name:

Hydrolase/inhibitor

Title:

Trypsin complexed with a modified sunflower trypsin inhibitor, sfti- tctr(n12,n14)

Structure:

Cationic trypsin. Chain: a. Synonym: beta-trypsin. Trypsin inhibitor 1. Chain: i. Engineered: yes. Mutation: yes. Other_details: cyclic peptide

Source:

Bos taurus. Bovine. Organism_taxid: 9913. Synthetic: yes. Helianthus annuus. Organism_taxid: 4232

Resolution:

1.93Å R-factor: 0.133 R-free: 0.158

Authors:

B.T.Riley,X.Chen

Key ref:

X.Chen et al. (2019). Potent, multi-target serine protease inhibition achieved by a simplified β-sheet motif. PLoS One, 14, e0210842. PubMed id: 30668585 DOI: 10.1371/journal.pone.0210842

Date:

13-Dec-17 Release date: 19-Dec-18

Protein chain

P00760  (TRY1_BOVIN) -  Serine protease 1 from Bos taurus

Seq: 246 a.a.

Struc: 223 a.a.

Protein chain

Q4GWU5  (SFTI1_HELAN) -  Trypsin inhibitor 1 from Helianthus annuus

Seq: 56 a.a.

Struc: 14 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chain A: E.C.3.4.21.4 - trypsin.
• Reaction: Preferential cleavage: Arg-|-Xaa, Lys-|-Xaa.

DOI no: 10.1371/journal.pone.0210842

PLoS One 14:e0210842 (2019)

PubMed id: 30668585

Potent, multi-target serine protease inhibition achieved by a simplified β-sheet motif.

X.Chen, B.T.Riley, S.J.de Veer, D.E.Hoke, J.Van Haeften, D.Leahy, J.E.Swedberg, M.Brattsand, P.J.Hartfield, A.M.Buckle, J.M.Harris.

ABSTRACT

Engagement of an extended β-sheet is a common substrate/inhibitor interaction at the active site of serine proteases and is an important feature of Laskowski mechanism inhibitors that present a substrate-like loop to a target protease. This loop is cleaved but subsequently relegated forming a stable inhibitor/protease complex. Laskowski inhibitors are ubiquitous in nature and are used extensively in serine protease inhibitor design. However, most studies concentrate on introducing new sidechain interactions rather than the direct contributions of the substrate-like β-sheet to enzyme inhibition. Here we report the crystal structure of an simplified β-sheet inhibitory motif within the Sunflower Trypsin Inhibitor (SFTI) in complex with trypsin. We show that the intramolecular hydrogen bond network of this SFTI variant (SFTI-TCTR) engages the inhibitor sidechains that would normally interact with a target protease, giving mainchain interactions a more prominent role in complex formation. Despite having reduced sidechain interactions, this SFTI variant is remarkably potent and inhibits a diverse range of serine proteases. Crystal structural analysis and molecular modelling of SFTI-TCTR complexes again indicates an interface dominated by β-sheet interactions, highlighting the importance of this motif and the adaptability of SFTI as a scaffold for inhibitor design.