2zhd

Exploring trypsin S3 pocketExploring trypsin S3 pocket

Structural highlights 2zhd is a 1 chain structure with sequence from Bos taurus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: , , , Related: 2zfs, 2zft, 3biv, 3biu, 2zda, 2zdk, 1k1p Activity: Trypsin, with EC number 3.4.21.4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed A congeneric series of benzamidine-type ligands with a central proline moiety and a terminal cycloalkyl group-linked by a secondary amine, ether, or methylene bridge-was synthesized as trypsin inhibitors. This series of inhibitors was investigated by isothermal titration calorimetry, crystal structure analysis in two crystal forms, and molecular dynamics simulations. Even though all of these congeneric ligands exhibited essentially the same affinity for trypsin, their binding profiles at the structural, dynamic, and thermodynamic levels are very distinct. The ligands display a pronounced enthalpy/entropy compensation that results in a nearly unchanged free energy of binding, even though individual enthalpy and entropy terms change significantly across the series. Crystal structures revealed that the secondary amine-linked analogs scatter over two distinct conformational families of binding modes that occupy either the inside or the outside the protein's S3/S4 specificity pocket. In contrast, the ether-linked and methylene-linked ligands preferentially occupy the hydrophobic specificity pocket. This also explains why the latter ligands could only be crystallized in the conformationally restricting closed crystal form whereas the derivative with the highest residual mobility in the series escaped our attempts to crystallize it in the closed form; instead, a well-resolved structure could only be achieved in the open form with the ligand in disordered orientation. These distinct binding modes are supported by molecular dynamics simulations and correlate with the shifting enthalpic/entropic signatures of ligand binding. The examples demonstrate that, at the molecular level, binding modes and thermodynamic binding signatures can be very different even for closely related ligands. However, deviating binding profiles provide the opportunity to optimally address a given target. Congeneric but Still Distinct: How Closely Related Trypsin Ligands Exhibit Different Thermodynamic and Structural Properties.,Brandt T, Holzmann N, Muley L, Khayat M, Wegscheid-Gerlach C, Baum B, Heine A, Hangauer D, Klebe G J Mol Biol. 2010 Nov 25. PMID:21111747 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Trypsin

spinqualitylabelsall models 2zhd, resolution 1.94Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image