4UFD: Thrombin In Complex With 4-(((1-((2s)-1-((2r)-2-( Benzylsulfonylamino)-3-phenyl-propanoyl)pyrrolidin-2-yl)-1- Oxo-ethyl)amino)methyl)benzamidine

Citation:
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.
PDB ID: 4UFDDownload
MMDB ID: 135897
PDB Deposition Date: 2015/3/16
Updated in MMDB: 2016/03
Experimental Method:
x-ray diffraction
Resolution: 1.43  Å
Source Organism:
Homo sapiens
Similar Structures:
Biological Unit for 4UFD: trimeric; determined by author and by software (PISA)
Molecular Components in 4UFD
Label Count Molecule
Proteins (3 molecules)
1
Thrombin Light Chain(Gene symbol: F2)
Molecule annotation
1
Thrombin Heavy Chain(Gene symbol: F2)
Molecule annotation
1
Hirudin Variant-2
Molecule annotation
Chemicals (7 molecules)
1
1
2
2
3
2
4
1
5
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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