PDBsum entry 4gux

Hydrolase/hydrolase inhibitor

PDB id: 4gux

Contents

Protein chains

223 a.a.

34 a.a.

Ligands

ACT ×2

Metals

_CA ×3

Waters ×1225

PDB id:

4gux

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of trypsin:mcoti-ii complex

Structure:

Cationic trypsin. Chain: a, b, c. Synonym: beta-trypsin, alpha-trypsin chain 1, alpha-trypsin chain 2. Trypsin inhibitor 2. Chain: d, e, f. Synonym: mcoti-ii, trypsin inhibitor ii

Source:

Bos taurus. Bovine,cow,domestic cattle,domestic cow. Organism_taxid: 9913. Momordica cochinchinensis. Spiny bitter cucumber. Organism_taxid: 3674

Resolution:

1.80Å R-factor: 0.162 R-free: 0.194

Authors:

G.J.King,N.L.Daly,L.Thorstholm,K.P.Greenwood,K.J.Rosengren,B.Heras, D.J.Craik,J.L.Martin

Key ref:

N.L.Daly et al. (2013). Structural insights into the role of the cyclic backbone in a squash trypsin inhibitor. J Biol Chem, 288, 36141-36148. PubMed id: 24169696 DOI: 10.1074/jbc.M113.528240

Date:

30-Aug-12 Release date: 04-Sep-13

Protein chains

P00760  (TRY1_BOVIN) -  Serine protease 1 from Bos taurus

Seq: 246 a.a.

Struc: 223 a.a.

Protein chains

P82409  (ITR2_MOMCO) -  Trypsin inhibitor 2 from Momordica cochinchinensis

Seq: 34 a.a.

Struc: 34 a.a.

Enzyme reactions

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

DOI no: 10.1074/jbc.M113.528240

J Biol Chem 288:36141-36148 (2013)

PubMed id: 24169696

Structural insights into the role of the cyclic backbone in a squash trypsin inhibitor.

N.L.Daly, L.Thorstholm, K.P.Greenwood, G.J.King, K.J.Rosengren, B.Heras, J.L.Martin, D.J.Craik.

ABSTRACT

MCoTI-II is a head-to-tail cyclic peptide with potent trypsin inhibitory activity and, on the basis of its exceptional proteolytic stability, is a valuable template for the design of novel drug leads. Insights into inhibitor dynamics and interactions with biological targets are critical for drug design studies, particularly for protease targets. Here, we show that the cyclization and active site loops of MCoTI-II are flexible in solution, but when bound to trypsin, the active site loop converges to a single well defined conformation. This finding of reduced flexibility on binding is in contrast to a recent study on the homologous peptide MCoTI-I, which suggested that regions of the peptide are more flexible upon binding to trypsin. We provide a possible explanation for this discrepancy based on degradation of the complex over time. Our study also unexpectedly shows that the cyclization loop, not present in acyclic homologues, facilitates potent trypsin inhibitory activity by engaging in direct binding interactions with trypsin.