PDBsum entry 4udw

Hydrolase

PDB id: 4udw

Contents

Protein chains

251 a.a.

11 a.a.

28 a.a.

Ligands

N6L

PO4

GOL

NAG

Metals

_NA ×2

Waters ×311

PDB id:

4udw

Name:

Hydrolase

Title:

Thrombin in complex with 1-(2r)-2-amino-3-phenyl-propanoyl-n-(2, 5dichlorophenyl)methylpyrrolidine-2-carboxamide

Structure:

Thrombin heavy chain. Chain: h. Fragment: thrombin heavy chain, unp residues 364-620. Synonym: coagulation factor ii, activation peptide fragment 1, activation peptide fragment 2, thrombin alpha. Hirudin variant-2. Chain: i. Fragment: unp residues 62-72. Engineered: yes.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Other_details: purified from human blood plasma. Synthetic: yes. Hirudo medicinalis. Medicinal leech. Organism_taxid: 6421. Other_details: purified from human blood plasma

Resolution:

1.16Å R-factor: 0.125 R-free: 0.141

Authors:

E.Ruehmann,A.Heine,G.Klebe

Key ref:

E.Rühmann et al. (2015). Fragment Binding Can Be Either More Enthalpy-Driven or Entropy-Driven: Crystal Structures and Residual Hydration Patterns Suggest Why. J Med Chem, 58, 6960-6971. PubMed id: 26270568 DOI: 10.1021/acs.jmedchem.5b00812

Date:

12-Dec-14 Release date: 26-Aug-15

Protein chain

P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens

Seq: 622 a.a.

Struc: 251 a.a.

Protein chain

P09945  (HIRV2_HIRME) -  Hirudin variant-2 (Fragment) from Hirudo medicinalis

Seq: 72 a.a.

Struc: 11 a.a.*

Protein chain

P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens

Seq: 622 a.a.

Struc: 28 a.a.

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

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

DOI no: 10.1021/acs.jmedchem.5b00812

J Med Chem 58:6960-6971 (2015)

PubMed id: 26270568

Fragment Binding Can Be Either More Enthalpy-Driven or Entropy-Driven: Crystal Structures and Residual Hydration Patterns Suggest Why.

E.Rühmann, M.Betz, A.Heine, G.Klebe.

ABSTRACT

In lead optimization, small, enthalpically advantaged fragments have been suggested to be superior, as an entropic component will be added inevitably during late-stage optimization. Determination of thermodynamic signatures of weak-binding fragments is essential to support the decision-making process, to decide which fragment to take to further optimization. High-resolution crystal structures of six fragments binding to the S1 pocket of thrombin were determined and analyzed with respect to their thermodynamic profile. The two most potent fragments exhibiting an amidine-type scaffold are not the most enthalpic binders; instead a chloro-thiophene fragment binds more enthalpically. Two chemically very similar chloro-aromatic fragments differ strongly in their potency (430 μM vs 10 mM); their binding modes are related, but the surrounding residual water network differs. The more potent one recruits a water molecule and involves Glu192 in binding, thus succeeding in firmly capping the S1 pocket. Fragments exhibiting a rather perfect solvation pattern in their binding mode also experience the highest potency.