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- PDB-1h8i: X-ray crystal structure of human alpha-thrombin with a tripeptide... -

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Basic information

Entry
Database: PDB / ID: 1h8i
TitleX-ray crystal structure of human alpha-thrombin with a tripeptide phosphonate inhibitor.
Components
  • (THROMBIN) x 2
  • HIRUDIN I
KeywordsHYDROLASE/HYDROLASE INHIBITOR / SERINE PROTEASE / HYDROLASE-HYDROLASE INHIBITOR COMPLEX
Function / homology
Function and homology information


negative regulation of serine-type peptidase activity / cytolysis by host of symbiont cells / thrombospondin receptor activity / Defective factor XII causes hereditary angioedema / thrombin / thrombin-activated receptor signaling pathway / negative regulation of astrocyte differentiation / regulation of blood coagulation / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / neutrophil-mediated killing of gram-negative bacterium ...negative regulation of serine-type peptidase activity / cytolysis by host of symbiont cells / thrombospondin receptor activity / Defective factor XII causes hereditary angioedema / thrombin / thrombin-activated receptor signaling pathway / negative regulation of astrocyte differentiation / regulation of blood coagulation / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / neutrophil-mediated killing of gram-negative bacterium / Defective F8 cleavage by thrombin / Platelet Aggregation (Plug Formation) / ligand-gated ion channel signaling pathway / positive regulation of collagen biosynthetic process / negative regulation of platelet activation / negative regulation of blood coagulation / positive regulation of blood coagulation / negative regulation of fibrinolysis / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / regulation of cytosolic calcium ion concentration / Gamma-carboxylation of protein precursors / Common Pathway of Fibrin Clot Formation / Removal of aminoterminal propeptides from gamma-carboxylated proteins / fibrinolysis / Intrinsic Pathway of Fibrin Clot Formation / negative regulation of proteolysis / negative regulation of cytokine production involved in inflammatory response / Peptide ligand-binding receptors / Regulation of Complement cascade / positive regulation of release of sequestered calcium ion into cytosol / acute-phase response / Cell surface interactions at the vascular wall / positive regulation of receptor signaling pathway via JAK-STAT / growth factor activity / lipopolysaccharide binding / serine-type endopeptidase inhibitor activity / positive regulation of insulin secretion / platelet activation / response to wounding / positive regulation of protein localization to nucleus / Golgi lumen / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / positive regulation of reactive oxygen species metabolic process / blood coagulation / antimicrobial humoral immune response mediated by antimicrobial peptide / regulation of cell shape / heparin binding / : / Thrombin signalling through proteinase activated receptors (PARs) / toxin activity / positive regulation of cell growth / blood microparticle / G alpha (q) signalling events / cell surface receptor signaling pathway / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor ligand activity / endoplasmic reticulum lumen / signaling receptor binding / serine-type endopeptidase activity / positive regulation of cell population proliferation / calcium ion binding / proteolysis / extracellular space / extracellular exosome / extracellular region / plasma membrane
Similarity search - Function
Hirudin / Proteinase inhibitor I14, hirudin / Thrombin inhibitor hirudin / Hirudin/antistatin / Prothrombin/thrombin / Thrombin light chain / Thrombin light chain domain superfamily / : / Thrombin light chain / Kringle domain ...Hirudin / Proteinase inhibitor I14, hirudin / Thrombin inhibitor hirudin / Hirudin/antistatin / Prothrombin/thrombin / Thrombin light chain / Thrombin light chain domain superfamily / : / Thrombin light chain / Kringle domain / Kringle / Kringle, conserved site / Kringle superfamily / Kringle domain signature. / Kringle domain profile. / Kringle domain / Vitamin K-dependent carboxylation/gamma-carboxyglutamic (GLA) domain / Gamma-carboxyglutamic acid-rich (GLA) domain / Gamma-carboxyglutamic acid-rich (GLA) domain superfamily / Vitamin K-dependent carboxylation domain. / Gla domain profile. / Domain containing Gla (gamma-carboxyglutamate) residues. / Kringle-like fold / Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Serine proteases, trypsin family, histidine active site. / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, serine active site. / Serine proteases, trypsin domain profile. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / Trypsin-like serine proteases / Thrombin, subunit H / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
Chem-PHV / Prothrombin / Hirudin variant-1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
HIRUDO MEDICINALIS (medicinal leech)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.75 Å
AuthorsSkordalakes, E. / Dodson, G.G. / Green, D. / Deadman, J.
Citation
Journal: J.Mol.Biol. / Year: 2001
Title: Inhibition of Human Alpha-Thrombin by a Phosphonate Tripeptide Proceeds Via a Metastable Pentacoordinated Phosphorus Intermediate
Authors: Skordalakes, E. / Dodson, G.G. / Green, D.S. / Goodwin, C.A. / Scully, M.F. / Hudson, H.R. / Kakkar, V.V. / Deadman, J.J.
#1: Journal: Biochemistry / Year: 1996
Title: Inhibition of Trypsin and Thrombin by Amino (4-Amidinophenyl)Methanephosphonate Diphenyl Ester Derivatives: X-Ray and Molecular Models
Authors: Bertrand, J.A. / Oleksyszyn, J. / Kam, C.M. / Boduszek, B. / Presnell, S. / Plaskon, R.R. / Suddath, F.L. / Powers, J.C. / Williams, L.D.
History
DepositionFeb 8, 2001Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 2, 2001Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Atomic model / Database references ...Atomic model / Database references / Derived calculations / Non-polymer description / Structure summary / Version format compliance
Revision 1.2Nov 30, 2012Group: Other
Revision 1.3Mar 13, 2013Group: Other
Revision 1.4Jul 12, 2017Group: Derived calculations / Category: struct_conn
Item: _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag ..._struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id
Revision 1.5May 22, 2019Group: Data collection / Refinement description / Category: refine / Item: _refine.pdbx_ls_cross_valid_method
Revision 1.6Dec 13, 2023Group: Advisory / Data collection ...Advisory / Data collection / Database references / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / pdbx_unobs_or_zero_occ_residues
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf
Revision 1.7Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: THROMBIN
I: HIRUDIN I
L: THROMBIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,3984
Polymers33,7613
Non-polymers6381
Water6,575365
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4430 Å2
ΔGint-15 kcal/mol
Surface area12550 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.393, 71.301, 72.416
Angle α, β, γ (deg.)90.00, 100.87, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11H-471-

HOH

21H-650-

HOH

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Components

#1: Protein THROMBIN / COAGULATION FACTOR II


Mass: 29208.572 Da / Num. of mol.: 1 / Fragment: THROMBIN HEAVY CHAIN / Source method: isolated from a natural source / Source: (natural) HOMO SAPIENS (human) / References: UniProt: P00734, thrombin
#2: Protein/peptide HIRUDIN I / LEPIRUDIN


Mass: 1363.399 Da / Num. of mol.: 1 / Fragment: RESIDUES 55 TO 64 / Source method: isolated from a natural source / Source: (natural) HIRUDO MEDICINALIS (medicinal leech) / References: UniProt: P01050
#3: Protein/peptide THROMBIN / COAGULATION FACTOR II


Mass: 3188.627 Da / Num. of mol.: 1 / Fragment: THROMBIN LIGHT CHAIN / Source method: isolated from a natural source / Source: (natural) HOMO SAPIENS (human) / References: UniProt: P00734, thrombin
#4: Chemical ChemComp-PHV / N-[(benzyloxy)carbonyl]-beta-phenyl-D-phenylalanyl-N-[(1S)-4-methoxy-1-phosphonobutyl]-L-prolinamide


Type: peptide-like / Mass: 637.660 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H40N3O8P
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 365 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.64 Å3/Da / Density % sol: 53 %
Crystal growpH: 7.2 / Details: PH 7.20
Crystal grow
*PLUS
pH: 7.3 / Method: vapor diffusion, hanging drop / Details: Skordalakes, E., (1997) J.Am.Chem.Soc., 119, 9935.
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-ID
125 %(w/v)PEG80001reservoir
20.05 Mammonium phosphate1reservoir
30.05 Msodium azide1reservoir

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Wavelength: 1.5418
DetectorDate: Jun 7, 1998
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.75→20 Å / Num. obs: 35239 / % possible obs: 98 % / Observed criterion σ(I): 5 / Redundancy: 3 % / Rmerge(I) obs: 0.062 / Rsym value: 0.075 / Net I/σ(I): 16
Reflection shellResolution: 1.75→1.75 Å / Redundancy: 2 % / Rmerge(I) obs: 0.21 / Mean I/σ(I) obs: 5 / Rsym value: 0.28 / % possible all: 97
Reflection
*PLUS
% possible obs: 98 %
Reflection shell
*PLUS
% possible obs: 96 % / Rmerge(I) obs: 0.23 / Mean I/σ(I) obs: 3

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Processing

Software
NameClassification
REFMACrefinement
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1HGT

1hgt


Resolution: 1.75→20 Å / Cross valid method: FREE R-VALUE / σ(F): 0
RfactorNum. reflection% reflection
Rfree0.235 --
Rwork0.186 --
obs-35239 98 %
Refinement stepCycle: LAST / Resolution: 1.75→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2368 0 44 365 2777
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONp_bond_d0.01
X-RAY DIFFRACTIONp_angle_d1.2
X-RAY DIFFRACTIONp_angle_deg
X-RAY DIFFRACTIONp_planar_d
X-RAY DIFFRACTIONp_hb_or_metal_coord
X-RAY DIFFRACTIONp_mcbond_it
X-RAY DIFFRACTIONp_mcangle_it
X-RAY DIFFRACTIONp_scbond_it
X-RAY DIFFRACTIONp_scangle_it
X-RAY DIFFRACTIONp_plane_restr
X-RAY DIFFRACTIONp_chiral_restr
X-RAY DIFFRACTIONp_singtor_nbd
X-RAY DIFFRACTIONp_multtor_nbd
X-RAY DIFFRACTIONp_xhyhbond_nbd
X-RAY DIFFRACTIONp_xyhbond_nbd
X-RAY DIFFRACTIONp_planar_tor
X-RAY DIFFRACTIONp_staggered_tor
X-RAY DIFFRACTIONp_orthonormal_tor
X-RAY DIFFRACTIONp_transverse_tor
X-RAY DIFFRACTIONp_special_tor
Software
*PLUS
Name: REFMAC / Classification: refinement
Refinement
*PLUS
Lowest resolution: 20 Å / Rfactor obs: 0.186
Solvent computation
*PLUS
Displacement parameters
*PLUS

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