2CF8

Complex of recombinant human thrombin with an inhibitor

Summary for 2CF8

• Entry DOI: 10.2210/pdb2cf8/pdb
• Related: 2CF9
• Related PRD ID: PRD_000481
• Descriptor: THROMBIN HEAVY CHAIN, HIRUDIN IIIA, THROMBIN LIGHT CHAIN, ... (7 entities in total)
• Functional Keywords: hydrolase/inhibitor, acute phase, blood coagulation, calcium-binding, glycoprotein, hydolase, serine protease, serine protease inhibitor complex, complex hydrolase-inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Secreted, extracellular space: P00734 P00734; Secreted: P28508
• Total number of polymer chains: 3
• Total formula weight: 34808.29

Authors

Schweizer, E.,Hoffmann-Roeder, A.,Olsen, J.A.,Obst-Sander, U.,Wagner, B.,Kansy, M.,Banner, D.W.,Diederich, F. (deposition date: 2006-02-17, release date: 2006-06-14, Last modification date: 2023-12-13)

Primary citation

Schweizer, E.,Hoffmann-Roeder, A.,Olsen, J.A.,Seiler, P.,Obst-Sander, U.,Wagner, B.,Kansy, M.,Banner, D.W.,Diederich, F.
Multipolar Interactions in the D Pocket of Thrombin: Large Differences between Tricyclic Imide and Lactam Inhibitors.
Org.Biomol.Chem., 4:2364-, 2006

PubMed Abstract: Two series of tricyclic inhibitors of the serine protease thrombin, imides (+/-)-1-(+/-)-8 and lactams (+/-)-9-(+/-)-13, were analysed to evaluate contributions of orthogonal multipolar interactions with the backbone C=O moiety of Asn98 to the free enthalpy of protein-ligand complexation. The lactam derivatives are much more potent and more selective inhibitors (K(i) values between 0.065 and 0.005 microM, selectivity for thrombin over trypsin between 361- and 1609-fold) than the imide compounds (Ki values between 0.057 and 23.7 microM, selectivity for thrombin over trypsin between 3- and 67-fold). The increase in potency and selectivity is explained by the favorable occupancy of the P-pocket of thrombin by the additional isopropyl substituent in the lactam derivatives. The nature of the substituent on the benzyl ring filling the D pocket strongly influences binding potency in the imide series, with Ki values increasing in the sequence: F < OCH2O < Cl < H < OMe < OH < N(pyr)<< Br. This sequence can be explained by both steric fit and the occurrence of orthogonal multipolar interactions with the backbone C[double bond, length as m-dash]O moiety of Asn98. In contrast, the substituent on the benzyl ring hardly affects the ligand potency in the lactam series. This discrepancy was clarified by the comparison of X-ray structures solved for co-crystals of thrombin with imide and lactam ligands. Whereas the benzyl substituents in the imide inhibitors are sufficiently close (< or =3.5 Angstroms) to the C=O group of Asn98 to allow for attractive orthogonal multipolar interactions, the distances in the lactam series are too large (> or =4 Angstroms) for attractive dipolar contacts to be effective.

PubMed: 16763681
DOI: 10.1039/B602585D

Experimental method

X-RAY DIFFRACTION (1.3 Å)