PDBsum entry 4lhh

Hydrolase/hydrolase inhibitor

PDB id: 4lhh

Contents

Protein chain

330 a.a.

Ligands

1TZ

GOL ×4

DMS ×3

ACT ×2

Waters ×333

PDB id:

4lhh

Name:

Hydrolase/hydrolase inhibitor

Title:

Endothiapepsin in complex with 2mm acylhydrazone inhibitor

Structure:

Endothiapepsin. Chain: a. Fragment: unp residues 90-419. Synonym: aspartate protease. Ec: 3.4.23.22

Source:

Cryphonectria parasitica. Chesnut blight fungus. Organism_taxid: 5116

Resolution:

1.73Å R-factor: 0.148 R-free: 0.176

Authors:

N.Radeva,A.Heine,G.Klebe

Key ref:

M.Mondal et al. (2014). Structure-based design of inhibitors of the aspartic protease endothiapepsin by exploiting dynamic combinatorial chemistry. Angew Chem Int Ed Engl, 53, 3259-3263. PubMed id: 24532096 DOI: 10.1002/anie.201309682

Date:

01-Jul-13 Release date: 02-Apr-14

Protein chain

P11838  (CARP_CRYPA) -  Endothiapepsin from Cryphonectria parasitica

Seq: 419 a.a.

Struc: 330 a.a.

Enzyme reactions

• Enzyme class: E.C.3.4.23.22 - endothiapepsin.
• Reaction: Hydrolysis of proteins with broad specificity similar to that of pepsin A, preferring hydrophobic residues at P1 and P1', but does not cleave 14-Ala-|-Leu-15 in the B chain of insulin or Z-Glu-Tyr. Clots milk.

DOI no: 10.1002/anie.201309682

Angew Chem Int Ed Engl 53:3259-3263 (2014)

PubMed id: 24532096

Structure-based design of inhibitors of the aspartic protease endothiapepsin by exploiting dynamic combinatorial chemistry.

M.Mondal, N.Radeva, H.Köster, A.Park, C.Potamitis, M.Zervou, G.Klebe, A.K.Hirsch.

ABSTRACT

Structure-based design (SBD) can be used for the design and/or optimization of new inhibitors for a biological target. Whereas de novo SBD is rarely used, most reports on SBD are dealing with the optimization of an initial hit. Dynamic combinatorial chemistry (DCC) has emerged as a powerful strategy to identify bioactive ligands given that it enables the target to direct the synthesis of its strongest binder. We have designed a library of potential inhibitors (acylhydrazones) generated from five aldehydes and five hydrazides and used DCC to identify the best binder(s). After addition of the aspartic protease endothiapepsin, we characterized the protein-bound library member(s) by saturation-transfer difference NMR spectroscopy. Cocrystallization experiments validated the predicted binding mode of the two most potent inhibitors, thus demonstrating that the combination of de novo SBD and DCC constitutes an efficient starting point for hit identification and optimization.