PDBsum entry 2zgb

Hydrolase/hydrolase inhibitor

PDB id: 2zgb

Contents

Protein chains

27 a.a. *

249 a.a. *

Ligands

ASP-PHE-GLU-GLU-ILE-PRO-GLU-GLU-TYS

21U

Metals

_NA ×2

Waters ×185

* Residue conservation analysis

PDB id:

2zgb

Name:

Hydrolase/hydrolase inhibitor

Title:

Thrombin inhibition

Structure:

Thrombin light chain. Chain: l. Synonym: coagulation factor ii. Thrombin heavy chain. Chain: h. Synonym: coagulation factor ii. Hirudin variant-1. Chain: i. Fragment: unp residues 54-64.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Tissue: blood plasma. Synthetic: yes. Hirudo medicinalis. Organism_taxid: 6421. Other_details: synthetic fragment of hirudin from hirudo medicinalis

Resolution:

1.60Å R-factor: 0.208 R-free: 0.242

Authors:

B.Baum,A.Heine,G.Klebe

Key ref:

B.Baum et al. (2010). Non-additivity of functional group contributions in protein-ligand binding: a comprehensive study by crystallography and isothermal titration calorimetry. J Mol Biol, 397, 1042-1054. PubMed id: 20156458

Date:

21-Jan-08 Release date: 16-Dec-08

Protein chain

P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens

Seq: 622 a.a.

Struc: 27 a.a.

Protein chain

P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens

Seq: 622 a.a.

Struc: 249 a.a.

Enzyme reactions

• Enzyme class: Chains L, H: E.C.3.4.21.5 - thrombin.
• Reaction: Preferential cleavage: Arg-|-Gly; activates fibrinogen to fibrin and releases fibrinopeptide A and B.

J Mol Biol 397:1042-1054 (2010)

PubMed id: 20156458

Non-additivity of functional group contributions in protein-ligand binding: a comprehensive study by crystallography and isothermal titration calorimetry.

B.Baum, L.Muley, M.Smolinski, A.Heine, D.Hangauer, G.Klebe.

ABSTRACT

Additivity of functional group contributions to protein-ligand binding is a very popular concept in medicinal chemistry as the basis of rational design and optimized lead structures. Most of the currently applied scoring functions for docking build on such additivity models. Even though the limitation of this concept is well known, case studies examining in detail why additivity fails at the molecular level are still very scarce. The present study shows, by use of crystal structure analysis and isothermal titration calorimetry for a congeneric series of thrombin inhibitors, that extensive cooperative effects between hydrophobic contacts and hydrogen bond formation are intimately coupled via dynamic properties of the formed complexes. The formation of optimal lipophilic contacts with the surface of the thrombin S3 pocket and the full desolvation of this pocket can conflict with the formation of an optimal hydrogen bond between ligand and protein. The mutual contributions of the competing interactions depend on the size of the ligand hydrophobic substituent and influence the residual mobility of ligand portions at the binding site. Analysis of the individual crystal structures and factorizing the free energy into enthalpy and entropy demonstrates that binding affinity of the ligands results from a mixture of enthalpic contributions from hydrogen bonding and hydrophobic contacts, and entropic considerations involving an increasing loss of residual mobility of the bound ligands. This complex picture of mutually competing and partially compensating enthalpic and entropic effects determines the non-additivity of free energy contributions to ligand binding at the molecular level.