PDBsum entry 3h8c

Hydrolase

PDB id: 3h8c

Contents

Protein chains

215 a.a. *

Ligands

NSZ ×2

Waters ×129

* Residue conservation analysis

PDB id:

3h8c

Name:

Hydrolase

Title:

A combined crystallographic and molecular dynamics study of cathepsin- l retro-binding inhibitors (compound 14)

Structure:

Cathepsin l1. Chain: a, b. Fragment: cathepsin l heavy chain and light chain, unp residues 114- 333. Synonym: major excreted protein, mep, cathepsin l1 heavy chain, cathepsin l1 light chain. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: cathepsin l. Expressed in: saccharomyces cerevisiae. Expression_system_taxid: 4932

Resolution:

2.50Å R-factor: 0.237 R-free: 0.292

Authors:

S.R.Tulsidas,S.F.Chowdhury,S.Kumar,L.Joseph,E.O.Purisima,J.Sivaraman

Key ref:

R.T.Shenoy et al. (2009). A combined crystallographic and molecular dynamics study of cathepsin L retrobinding inhibitors. J Med Chem, 52, 6335-6346. PubMed id: 19761244

Date:

29-Apr-09 Release date: 20-Oct-09

Protein chains

P07711  (CATL1_HUMAN) -  Procathepsin L from Homo sapiens

Seq: 333 a.a.

Struc: 215 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.3.4.22.15 - cathepsin L.
• Reaction: Specificity close to that of papain. As compared to cathepsin B, cathepsin L exhibits higher activity towards protein substrates, but has little activity on Z-Arg-Arg-NHMec, and no peptidyl-dipeptidase activity.

J Med Chem 52:6335-6346 (2009)

PubMed id: 19761244

A combined crystallographic and molecular dynamics study of cathepsin L retrobinding inhibitors.

R.T.Shenoy, S.F.Chowdhury, S.Kumar, L.Joseph, E.O.Purisima, J.Sivaraman.

ABSTRACT

We report the crystal structures of three noncovalent retrobinding inhibitors in complex with mature cathepsin L up to resolutions of 2.5, 1.8, and 2.5 A, respectively. These inhibitors were Bpa-(Nepsilon-Bpa)Lys-DArg-Tyr-Npe, Bpa-(Nepsilon-Bpa)Lys-DArg-Phe-Npe, and Bpa-MCys-DArg-Phe-Npe, where Bpa = biphenylacetyl and Pea = N-phenylethyl. These were selected to clarify the binding mode of the biphenyl groups in the S' subsites because the addition of a second biphenyl does not improve potency. Examination of the symmetry-related monomers in the crystal structures revealed inhibitor-inhibitor crystal packing interactions. Molecular dynamics simulations were then used to explore the structure and dynamical behavior of the isolated protein-ligand complexes in solution. In the simulations, the backbone biphenyl groups for all three inhibitors ended up in the same location despite having started out in different orientations in the initial crystal structure conformations. The lack of improved potency of the larger inhibitors over the smaller one is attributed to a correspondingly greater entropic cost of binding.