A novel serine protease inhibition motif involving a multi-centered short hydrogen bonding network at the active site

Journal of Molecular Biology

Volumn 307, Issue 5, 2001, Pages 1451-1486

  Katz, Bradley A ^a   Elrod, Kyle ^a   Luong, Christine ^a   Rice, Mark J ^a   Mackman, Richard L ^a   Sprengeler, Paul A ^a   Spencer, Jeffrey ^a   Hataye, Jason ^a   Janc, James ^a   Link, John ^a   Litvak, Joane ^a   Rai, Roopa ^a   Rice, Ken ^a   Sideris, Steve ^a   Verner, Erik ^a   Young, Wendy ^a  

^a Axys Pharmaceuticals Inc   (United States)

Author keywords

oxyanion hole water; Shift of pKaof His57; Structure based drug design; Three centered very short hydrogen bond

Indexed keywords

2 (2 PHENOL)BENZIMIDAZOLE; 2 (2 PHENOL)INDOLE; APC 10273; APC 1144; APC 13140; APC 13417; APC 1801; APC 1802; APC 1847; APC 6669; APC 8249; APC 8328; BENZAMIDINE; HISTIDINE; HYDROXAMIC ACID DERIVATIVE; PHENOL DERIVATIVE; SERINE PROTEINASE; SERINE PROTEINASE INHIBITOR; THROMBIN; TRYPSIN; UNCLASSIFIED DRUG; UROKINASE; WATER; ZINC COMPLEX; ZINC ION;

ARTICLE; CRYSTAL STRUCTURE; DRUG DESIGN; DRUG SOLUBILITY; ENZYME ACTIVE SITE; ENZYME INHIBITION; HYDROGEN BOND; IONIZATION; PH; PKA; PRIORITY JOURNAL; PROTEIN MOTIF; PROTON TRANSPORT; THERMODYNAMICS;

EID: 0035853282     PISSN: 00222836     EISSN: None     Source Type: Journal    
DOI: 10.1006/jmbi.2001.4516     Document Type: Article

References (71)

1. Des̊ign of potent selective zinc-mediated serine protease inhibitors
2. 2+to mediate potent, specific inhibition of serine proteases
3. A novel approach to serine protease inhibition: Kinetic characterization of inhibitors whose potencies and selectivities are dramatically enhanced by zinc(II)
4. The relevance of tumor pH to the treatment of malignant disease
5. Noninvasive measurement of interstitial pH profiles in normal and neoplastic tissue using fluorescence ratio imaging microscopy
6. Cellular pH gradient in tumor versus normal tissue: Potential exploitation for the treatment of cancer
7. A reaction-diffused model of cancer invasion
8. Tumor pH: Implications for treatment and novel drug design
9. Low-barrier hydrogen bonds and enzymic catalysis
10. A short hydrogen bond provides only moderate stabilization of an enzyme-inhibitor complex of citrate synthase
11. On low-barrier hydrogen bonds and enzyme catalysis
12. amatching on binding affinity and hydrogen bond length
13. Short strong hydrogen bonds: Can they explain enzymic catalysis?
14. Energetics of a low barrier hydrogen bond in nonpolar solvents
15. The energetics of hydrogen bonds in model systems. Implication for enzymatic catalysis
16. The change in hydrogen bond strength accompanying charge rearrangement: Implications for enzymatic catalysis
17. Energy considerations show that low-barrier hydrogen bonds do not offer a catalytic advantage over ordinary hydrogen bonds
18. A low-barrier hydrogen bond in the catalytic triad of serine proteases? Theory versus experiment
19. A low energy short hydrogen bond in very high-resolution structures of protein receptor-phosphate complexes
20. The low-barrier hydrogen bond in enzyme catalysis
21. Characterization of low-barrier hydrogen bonds. 8. Substituent effects on the strength and geometry of the formic acid-formate anion model system. An ab initio and DFT investigation
22. Characterization of low-barrier hydrogen bonds. 6. Cavity polarity effects on the formic acid-formate anion model system. An ab initio and DFT investigation
23. On the electronic nature of low-barrier hydrogen bonds in enzymatic reactions
24. Electrostatic origin of the catalytic power of enzymes and the role of preorganized active sites
25. Structures of two thermolysin-inhibitor complexes that differ by a single hydrogen bond
26. Comparison of the structures of three carboxypeptidase A-phosphonate complexes determined by X-ray crystallography
27. Crystallographic analysis of transition-state mimics bound to penicillopepsin: Phosphorus-containing peptide analogs
28. Structure-based design tools: Structural and thermodynamic comparison with biotin of a small molecule that binds to streptavidin with micromolar affinity
29. Preparation, characterization, and the crystal structure of the inhibitor ZK-807834 (CI-1031) complexed with factor Xa
30. pH affects both the mechanism and the specificity of peptide binding to a class II major histocompatibility complex molecule
31. pH dependence of ligand binding to D2 dopamine receptors
32. Analysis of the pH dependence of the neonatal Fc receptor/immunoglobulin G interaction using antibody and receptor variants
33. Binding of biotin to streptavidin stabilizes intersubunit salt bridges between Asp61 and His87 at low pH
34. aof the peptide histidine is less than 3.0
35. Complex of α-chymotrypsin and N-acetyl-L-leucyl-L-phenylalanyl trifluoromethyl ketone: Structural studies with NMR spectroscopy
36. A study of the stabilization of tetrahedral adducts by trypsin and Δ-chymotrypsin
37. 13C-NMR study of the role of Asn-155 in stabilizing the oxyanion of a subtilisin tetrahedral adduct
38. Derivatives of 5-amidine indole as inhibitors of thrombin catalytic activity
39. Very strong hydrogen bonding
40. Hydrogen bonding and chemical reactivity
41. Strong" hydrogen bonds in chemistry and biology
42. Structural basis for selectivity of a small molecule, S1-binding, submicromolar inhibitor of urokinase-type plasminogen activator
43. Covalent nature of the strong homonuclear hydrogen bond. Study of the O-H - O system by crystal structure correlation methods
44. A low barrier hydrogen bond in the catalytic triad of serine proteases
45. 2)anion. A short, symmetric hydrogen bond
46. A simple method for determining the relative strengths of normal and low-barrier hydrogen bonds in solution: Implications for enzyme catalysis
47. Bond dissociation energies of F2and HF2A gas-phase experimental and G2 theoretical study
48. Attack of zwitterionic ammonium thiolates on a distorted anilide as a model for the acylation of papain by amides. A simple demonstration of a bell-shaped pH/rate profile
49. Prediction of pH-dependent properties of proteins
50. achanges in a protein tyrosine phosphatase: Experimental and theoretical determination of electrostatic properties in a small protein
51. A pH-dependent stabilization of an active site loop observed from low and high pH crystal structures of mutant monomeric glycinamide ribonucleotide transformylase at 1.8 to 1.9 Å
52. Neutral imidazole is the electrophile in the reaction catalyzed by triose-phosphate isomerase: Structural origins and catalytic implications
53. A new concept for the mechanism of action of chymotrypsin: The role of the low-barrier hydrogen bond
54. Binding energy, specificity, and enzyme catalysis: The circe effect
55. Linear free energy analysis of hydrogen bonding in proteins
56. amatching and environmental effects on the strengths of hydrogen bonds and their potential roles in enzymatic catalysis
57. Just add water! The effect of water on the specificity of protein-ligand binding sites and its potential application to drug design
58. Structure of the hirugen and hirulog 1 complexes of alpha-thrombin
59. The structure and specific binding of trypsin: A comparison of inhibited derivatives and a model for substrate binding
60. The refined crystal structure of bovine beta-trypsin at 1.8 Å resolution. II. Crystallographic refinement, calcium binding site, benzamidine binding site and active site at pH 7.0
61. Structure of bovine trypsinogen at 1.9 Å resolution
62. Structure of an acyl-enzyme intermediate during catalysis: (guanidinobenzoyl)-trypsin
63. i∼ nanomolar inhibitors of serine proteases by binding or epitaxial chemistry on an enzyme surface
64. Structural and functional analyses of benzamidine-based inhibitors of factor Xa, tPA, and urokinase
65. The free R value: A novel statistical quantity for assessing the accuracy of crystal structures
66. High-throughput screening of enzyme inhibitors: Automatic determination of tight-binding inhibition constants
67. adetermination of water-insoluble substances
68. Interlaboratory study of log P determination by shake-flask and potentiometric methods