3Q00

Bovine trypsin variant X(tripleGlu217Ile227) in complex with small molecule inhibitor

Summary for 3Q00

• Entry DOI: 10.2210/pdb3q00/pdb
• Related: 1V2K 3PLK 3PLP 3PM3 3PWB 3PWC 3PYH
• Related PRD ID: PRD_001008
• Descriptor: Cationic trypsin, CALCIUM ION, N~2~-(benzylsulfonyl)-D-arginyl-N-(4-carbamimidoylbenzyl)glycinamide, ... (6 entities in total)
• Functional Keywords: trypsin-like serine protease, hydrolase, protein binding, duodenum, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Bos taurus (bovine)
• Cellular location: Secreted, extracellular space: P00760
• Total number of polymer chains: 1
• Total formula weight: 25388.68

Authors

Tziridis, A.,Neumann, P.,Kolenko, P.,Stubbs, M.T. (deposition date: 2010-12-15, release date: 2011-12-21, Last modification date: 2024-10-16)

Primary citation

Tziridis, A.,Rauh, D.,Neumann, P.,Kolenko, P.,Menzel, A.,Brauer, U.,Ursel, C.,Steinmetzer, P.,Sturzebecher, J.,Schweinitz, A.,Steinmetzer, T.,Stubbs, M.T.
Correlating structure and ligand affinity in drug discovery: a cautionary tale involving second shell residues.
Biol.Chem., 395:891-903, 2014

PubMed 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.

PubMed: 25003390
DOI: 10.1515/hsz-2014-0158

Experimental method

X-RAY DIFFRACTION (1.7 Å)