PDBsum entry 3v12

Hydrolase/hydrolase inhibitor

PDB id: 3v12

Contents

Protein chain

223 a.a.

Ligands

PMJ

SO4 ×2

GOL

Metals

_CA

Waters ×267

PDB id:

3v12

Name:

Hydrolase/hydrolase inhibitor

Title:

Bovine trypsin variant x(tripleglu217phe227) in complex with small molecule inhibitor

Structure:

Cationic trypsin. Chain: a. Synonym: beta-trypsin, alpha-trypsin chain 1, alpha-trypsin chain 2. Engineered: yes. Mutation: yes

Source:

Bos taurus. Bovine. Organism_taxid: 9913. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.80Å R-factor: 0.191 R-free: 0.236

Authors:

A.Tziridis,P.Neumann,P.Kolenko,M.T.Stubbs

Key ref:

A.Tziridis et al. (2014). Correlating structure and ligand affinity in drug discovery: a cautionary tale involving second shell residues. Biol Chem, 395, 891-903. PubMed id: 25003390 DOI: 10.1515/hsz-2014-0158

Date:

09-Dec-11 Release date: 12-Dec-12

Protein chain

P00760  (TRY1_BOVIN) -  Serine protease 1 from Bos taurus

Seq: 246 a.a.

Struc: 223 a.a.*

* PDB and UniProt seqs differ at 10 residue positions (black crosses)

Enzyme reactions

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

DOI no: 10.1515/hsz-2014-0158

Biol Chem 395:891-903 (2014)

PubMed id: 25003390

Correlating structure and ligand affinity in drug discovery: a cautionary tale involving second shell residues.

A.Tziridis, D.Rauh, P.Neumann, P.Kolenko, A.Menzel, U.Bräuer, C.Ursel, P.Steinmetzer, J.Stürzebecher, A.Schweinitz, T.Steinmetzer, M.T.Stubbs.

ABSTRACT

Abstract A high-resolution crystallographic structure determination of a protein-ligand complex is generally accepted as the 'gold standard' for structure-based drug design, yet the relationship between structure and affinity is neither obvious nor straightforward. Here we analyze the interactions of a series of serine proteinase inhibitors with trypsin variants onto which the ligand-binding site of factor Xa has been grafted. Despite conservative mutations of only two residues not immediately in contact with ligands (second shell residues), significant differences in the affinity profiles of the variants are observed. Structural analyses demonstrate that these are due to multiple effects, including differences in the structure of the binding site, differences in target flexibility and differences in inhibitor binding modes. The data presented here highlight the myriad competing microscopic processes that contribute to protein-ligand interactions and emphasize the difficulties in predicting affinity from structure.