4UFE

Thrombin in complex with (2R)-2-(benzylsulfonylamino)-N-(2-((4- carbamimidoylphenyl)methylamino)-2-oxo-butyl)-3-phenyl-propanamide

Summary for 4UFE

• Entry DOI: 10.2210/pdb4ufe/pdb
• Related: 4UFD 4UFF 4UFG
• Descriptor: THROMBIN HEAVY CHAIN, HIRUDIN VARIANT-2, THROMBIN LIGHT CHAIN, ... (8 entities in total)
• Functional Keywords: hydrolase, hydrolase inhibitor complex, serine protease, blood coagulation, blood clotting, convertion of fibrinogen to fibrin, blood clotting inhibitor, thrombin inhibitor, preorganization, glycosylation, blood
• Biological source: HOMO SAPIENS (HUMAN); More
• Total number of polymer chains: 3
• Total formula weight: 35516.30

Authors

Ruehmann, E.,Heine, A.,Klebe, G. (deposition date: 2015-03-16, release date: 2016-01-27, Last modification date: 2024-11-13)

Primary citation

Ruhmann, E.H.,Rupp, M.,Betz, M.,Heine, A.,Klebe, G.
Boosting Affinity by Correct Ligand Preorganization for the S2 Pocket of Thrombin: A Study by Isothermal Titration Calorimetry, Molecular Dynamics, and High-Resolution Crystal Structures.
Chemmedchem, 11:309-, 2016

PubMed Abstract: Structural preorganization to fix bioactive conformations at protein binding sites is a popular strategy to enhance binding affinity during late-stage optimization. The rationale for this enhancement relates to entropic advantages assigned to rigidified versus flexible ligands. We analyzed a narrow series of peptidomimetics binding to thrombin. The individual ligands exhibit at P2 a conformationally flexible glycine, more restricted alanine, N-methylglycine, N-methylhomoalanine, and largely rigidified proline moiety. Overall, affinity was found to increase by a factor of 1000, explained partly by an entropic advantage. All ligands adopt the same binding mode with small deviations. The residual mobility of the bound ligands is decreased across the series, and a protein side chain differs in its order/disorder behavior along with changes in the surface-water network pattern established across the newly generated protein-ligand surfaces. The enthalpy/entropy inventory displays a rather complex picture and emphasizes that thermodynamics can only be compared in terms of relative differences within a structurally similar ligand series.

PubMed: 26762840
DOI: 10.1002/CMDC.201500531

Experimental method

X-RAY DIFFRACTION (1.593 Å)