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- PDB-1mq5: Crystal Structure of 3-chloro-N-[4-chloro-2-[[(4-chlorophenyl)ami... -

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Basic information

Entry
Database: PDB / ID: 1mq5
TitleCrystal Structure of 3-chloro-N-[4-chloro-2-[[(4-chlorophenyl)amino]carbonyl]phenyl]-4-[(4-methyl-1-piperazinyl)methyl]-2-thiophenecarboxamide Complexed with Human Factor Xa
Components(COAGULATION FACTOR X ...Factor X) x 2
KeywordsBLOOD CLOTTING / PROTEIN INHIBITOR COMPLEX / COAGULATION COFACTOR / PROTEASE
Function / homology
Function and homology information


coagulation factor Xa / Defective factor IX causes thrombophilia / Defective cofactor function of FVIIIa variant / Defective F9 variant does not activate FX / Extrinsic Pathway of Fibrin Clot Formation / positive regulation of TOR signaling / Gamma-carboxylation of protein precursors / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / Common Pathway of Fibrin Clot Formation / Removal of aminoterminal propeptides from gamma-carboxylated proteins ...coagulation factor Xa / Defective factor IX causes thrombophilia / Defective cofactor function of FVIIIa variant / Defective F9 variant does not activate FX / Extrinsic Pathway of Fibrin Clot Formation / positive regulation of TOR signaling / Gamma-carboxylation of protein precursors / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / Common Pathway of Fibrin Clot Formation / Removal of aminoterminal propeptides from gamma-carboxylated proteins / Intrinsic Pathway of Fibrin Clot Formation / phospholipid binding / Golgi lumen / blood coagulation / positive regulation of cell migration / endoplasmic reticulum lumen / external side of plasma membrane / serine-type endopeptidase activity / calcium ion binding / proteolysis / extracellular space / extracellular region / plasma membrane
Similarity search - Function
Peptidase S1A, coagulation factor VII/IX/X/C/Z / Coagulation factor-like, Gla domain superfamily / Coagulation Factor Xa inhibitory site / Laminin / Laminin / EGF-type aspartate/asparagine hydroxylation site / EGF-like domain / EGF-like calcium-binding, conserved site / Calcium-binding EGF-like domain signature. / Aspartic acid and asparagine hydroxylation site. ...Peptidase S1A, coagulation factor VII/IX/X/C/Z / Coagulation factor-like, Gla domain superfamily / Coagulation Factor Xa inhibitory site / Laminin / Laminin / EGF-type aspartate/asparagine hydroxylation site / EGF-like domain / EGF-like calcium-binding, conserved site / Calcium-binding EGF-like domain signature. / Aspartic acid and asparagine hydroxylation site. / EGF-like calcium-binding domain / Calcium-binding EGF-like 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. / Epidermal growth factor-like domain. / EGF-like domain profile. / EGF-like domain signature 2. / EGF-like domain signature 1. / EGF-like domain / Ribbon / Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, histidine active site. / Serine proteases, trypsin domain profile. / Serine proteases, trypsin family, serine active site. / 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-XLC / Coagulation factor X
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / DIRECT REPLACEMENT / Resolution: 2.1 Å
AuthorsAdler, M. / Whitlow, M.
Citation
Journal: Biochemistry / Year: 2002
Title: Crystal Structures of Two Potent Nonamidine Inhibitors Bound to Factor Xa
Authors: Adler, M. / Kochanny, M.J. / Bin, Y. / Rumennik, G. / Light, D.L. / Biancalana, S. / Whitlow, M.
#1: Journal: Biochemistry / Year: 2000
Title: Preparation, Characterization and the Crystal Structure of the Inhibitor Zk-807834 (Ci-1031) Complexed with Factor Xa
Authors: Adler, M. / Davey, D.D. / Phillips, G.B. / Kim, S.H. / Jancarik, J. / Rumennik, G. / Light, D.L. / Whitlow, M.
#2: Journal: J.Med.Chem. / Year: 2000
Title: Crystal Structures of Human Factor Xa Complexed with Potent Inhibitors
Authors: Maignan, S. / Guilloteau, J.P. / Pouzieux, S. / Choi-Sledeski, Y.M. / Becker, M.R. / Klein, S.I. / Ewing, W.R. / Pauls, H.W. / Spada, A.P. / Mikol, V.
#3: Journal: J.Med.Chem. / Year: 1998
Title: Discovery of N-[2-[5-[Amino(imino)methyl]-2-hydroxyphenoxy]-3,5-difluoro- 6-[3-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenoxy]pyridin-4-yl]-N-methylglycine (ZK-807834): A Potent, Selective, ...Title: Discovery of N-[2-[5-[Amino(imino)methyl]-2-hydroxyphenoxy]-3,5-difluoro- 6-[3-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenoxy]pyridin-4-yl]-N-methylglycine (ZK-807834): A Potent, Selective, and Orally Active Inhibitor of the Blood Coagulation Enzyme Factor Xa
Authors: Phillips, G.B. / Buckman, B.O. / Davey, D.D. / Eagen, K.A. / Guilford, W.J. / Hinchman, J. / Ho, E. / Koovakkat, S. / Liang, A.M. / Light, D.R. / Mohan, R. / Ng, H.P. / Post, J.M. / Shaw, K. ...Authors: Phillips, G.B. / Buckman, B.O. / Davey, D.D. / Eagen, K.A. / Guilford, W.J. / Hinchman, J. / Ho, E. / Koovakkat, S. / Liang, A.M. / Light, D.R. / Mohan, R. / Ng, H.P. / Post, J.M. / Shaw, K.J. / Smith, D. / Subramanyam, B. / Sullivan, M.E. / Trinh, L. / Vergona, R. / Walters, J. / White, K. / Whitlow, M. / Wu, S. / Xu, W. / Morrissey, M.M.
History
DepositionSep 13, 2002Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 28, 2003Provider: repository / Type: Initial release
Revision 1.1Apr 28, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Non-polymer description / Version format compliance
Revision 1.3Oct 11, 2017Group: Advisory / Refinement description / Category: pdbx_unobs_or_zero_occ_atoms / software
Remark 300 BIOMOLECULE: 1 THIS ENTRY CONTAINS THE CRYSTALLOGRAPHIC ASYMMETRIC UNIT WHICH CONSISTS OF 2 ... BIOMOLECULE: 1 THIS ENTRY CONTAINS THE CRYSTALLOGRAPHIC ASYMMETRIC UNIT WHICH CONSISTS OF 2 CHAIN(S). FACTOR XA FORMS A COMPLEX WITH FACTOR VA IN THE PRESENCE OF CALCIUM AND A PHOSPHOLIPID MEMBRANE TO PRODUCE THE PROTHROMBINASE COMPLEX. THIS ENTRY CONTAINS THE EPIDERMAL GROWTH FACTOR LIKE DOMAIN 2(L) AND THE CATALYTIC DOMAIN (A) OF FACTOR XA IN THE CRYSTALLOGRAPHIC ASYMMETRIC UNIT. THE COORDINATES DO NOT CONTAIN THE GLA DOMAIN OR THE EPIDERMAL GROWTH FACTOR LIKE DOMAIN 1 OF FACTOR XA. ALTHOUGH THE ASYMMETRIC UNIT CONTAINS A FUNCTIONAL PROTEASE, IT DOES HAVE THE SAME SPECIFICITY AS THE PROTHROMBINASE COMPLEX. SEE REMARK 350 FOR INFORMATION ON GENERATING THE BIOLOGICAL MOLECULE(S).

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: COAGULATION FACTOR X HEAVY CHAIN
L: COAGULATION FACTOR X LIGHT CHAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,6607
Polymers31,8062
Non-polymers8545
Water3,099172
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3690 Å2
ΔGint-39 kcal/mol
Surface area12510 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.363, 72.018, 78.922
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
DetailsFactor Xa forms a complex with factor Va in the presence of calcium and a phospholipid membrane to produce the prothrombinase complex.

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Components

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COAGULATION FACTOR X ... , 2 types, 2 molecules AL

#1: Protein COAGULATION FACTOR X HEAVY CHAIN / Factor X / stuart factor


Mass: 26346.000 Da / Num. of mol.: 1 / Fragment: CATALYTIC DOMAIN / Source method: isolated from a natural source / Details: EXTRACTED FROM BLOOD / Source: (natural) Homo sapiens (human) / References: UniProt: P00742, coagulation factor Xa
#2: Protein COAGULATION FACTOR X LIGHT CHAIN / Factor X / stuart factor


Mass: 5460.121 Da / Num. of mol.: 1 / Fragment: EPIDERMAL GROWTH FACTOR LIKE DOMAIN 2 / Source method: isolated from a natural source / Details: EXTRACTED FROM BLOOD / Source: (natural) Homo sapiens (human) / References: UniProt: P00742, coagulation factor Xa

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Non-polymers , 4 types, 177 molecules

#3: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#4: Chemical ChemComp-XLC / 3-CHLORO-N-[4-CHLORO-2-[[(4-CHLOROPHENYL)AMINO]CARBONYL]PHENYL]-4-[(4-METHYL-1-PIPERAZINYL)METHYL]-2-THIOPHENECARBOXAMIDE


Mass: 537.889 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H23Cl3N4O2S
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 172 / Source method: isolated from a natural source / Formula: H2O

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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: 2.44 Å3/Da / Density % sol: 51.2 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: A THREE-FOLD EXCESS OF A PROPRIETARY FACTOR XA INHIBITOR WITH PICOMOLAR AFFINITY WAS ADDED TO THE DES-GLA-FACTOR XA. THIS INHIBITOR IS BASED ON THE SAME TEMPLATE AS XLC IN 1MQ5. THE PROTEIN ...Details: A THREE-FOLD EXCESS OF A PROPRIETARY FACTOR XA INHIBITOR WITH PICOMOLAR AFFINITY WAS ADDED TO THE DES-GLA-FACTOR XA. THIS INHIBITOR IS BASED ON THE SAME TEMPLATE AS XLC IN 1MQ5. THE PROTEIN WAS THEN CONCENTRATED TO 12-17 MG/ML. CRYSTALS WERE GROWN USING 2 UL OF COMPLEX WITH 2 UL OF RESERVOIR CONTAINING 15-21% PEG1500 AND 10 MM CACL2. 30-40 UL SITTING DROPS CONTAINING SATURATED INHIBITOR (5 MM) IN 21% PEG1500, 5 MM CACL2, 50 MM NACL, 50 MM TRIS PH 7.5 (CRYSTAL SOAKING SOLUTION) WERE EQUILIBRATED OVER A 1 ML RESERVOIR CONTAINING THE CRYSTAL SOAKING SOLUTION FOR 1 TO 2 DAYS. A SINGLE FACTOR XA CRYSTAL WAS TRANSFERRED USING A MOUNTED CRYOLOOP INTO ONE OF THESE SITTING DROPS AND ALLOWED TO SOAK FOR THREE OR MORE Days. AFTER THE INITIAL SOAK, EACH CRYSTAL WAS THEN TRANSFERRED TO AN UNUSED DROP AND ALLOWED TO SOAK FOR SECOND PERIOD OF THREE OR MORE DAYS. pH 7.50, VAPOR DIFFUSION, HANGING DROP, temperature 293K
Crystal grow
*PLUS
Details: Adler, M., (2000) Biochemistry, 39, 12534.
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDChemical formulaDetails
112 mg/mlprotein1drop
215-21 %PEG15001reservoir
310 mM1reservoirCaCl2
4inhibitor1drop3-fold excess
51dropHCl1 equiv

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL7-1 / Wavelength: 1.08 / Wavelength: 1.08 Å
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Dec 6, 2000
RadiationMonochromator: SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength
IDWavelength (Å)Relative weight
11.081
21.081
ReflectionResolution: 2.1→25 Å / Num. all: 18977 / Num. obs: 18977 / % possible obs: 98.4 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.6 % / Biso Wilson estimate: 30.79 Å2 / Rsym value: 0.054 / Net I/σ(I): 12
Reflection shellResolution: 2.1→2.15 Å / Redundancy: 3.7 % / Mean I/σ(I) obs: 2.2 / Num. unique all: 1366 / Rsym value: 0.395 / % possible all: 97.3
Reflection
*PLUS
Highest resolution: 2.1 Å / Lowest resolution: 25 Å / % possible obs: 98.2 % / Redundancy: 3.6 % / Rmerge(I) obs: 0.054
Reflection shell
*PLUS
Lowest resolution: 2.19 Å / % possible obs: 97.5 % / Rmerge(I) obs: 0.338 / Mean I/σ(I) obs: 2.2

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Processing

Software
NameVersionClassification
MAR345data collection
MOSFLMdata reduction
X-PLOR3.1model building
X-PLOR3.1refinement
X-PLOR3.1phasing
RefinementMethod to determine structure: DIRECT REPLACEMENT
Starting model: pdb entry 1FJS

1fjs


Resolution: 2.1→8 Å / Isotropic thermal model: isotropic / σ(F): 2 / σ(I): 0 / Stereochemistry target values: Engh & Huber
Details: FINAL REFINEMENT HAD A 600 TO 300 DEGREE SIMULATED ANNEALING, FOLLOWED BY A POWELL MINIMIZATION, B FACTOR OPTIMIZATION AND A FINAL POWELL MINIMIZATION.
RfactorNum. reflection% reflectionSelection details
Rfree0.264 720 4 %RANDOM
Rwork0.19 ---
obs0.1926 18602 98.2 %-
all-18977 --
Displacement parametersBiso mean: 31.18 Å2
Baniso -1Baniso -2Baniso -3
1--3.5382 Å20 Å20 Å2
2--4.9249 Å20 Å2
3----1.3866 Å2
Refinement stepCycle: LAST / Resolution: 2.1→8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2220 0 53 172 2445
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONx_bond_d0.011
X-RAY DIFFRACTIONx_bond_d_na
X-RAY DIFFRACTIONx_bond_d_prot
X-RAY DIFFRACTIONx_angle_d
X-RAY DIFFRACTIONx_angle_d_na
X-RAY DIFFRACTIONx_angle_d_prot
X-RAY DIFFRACTIONx_angle_deg2.02
X-RAY DIFFRACTIONx_angle_deg_na
X-RAY DIFFRACTIONx_angle_deg_prot
X-RAY DIFFRACTIONx_dihedral_angle_d
X-RAY DIFFRACTIONx_dihedral_angle_d_na
X-RAY DIFFRACTIONx_dihedral_angle_d_prot
X-RAY DIFFRACTIONx_improper_angle_d1.56
X-RAY DIFFRACTIONx_improper_angle_d_na
X-RAY DIFFRACTIONx_improper_angle_d_prot
X-RAY DIFFRACTIONx_mcbond_it1.5
X-RAY DIFFRACTIONx_mcangle_it2
X-RAY DIFFRACTIONx_scbond_it2
X-RAY DIFFRACTIONx_scangle_it2.5
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 8

Resolution (Å)Rfactor RfreeNum. reflection Rfree% reflection Rfree (%)Rfactor RworkNum. reflection RworkNum. reflection obs
2.1-2.190.3439914.10.28421202120
2.19-2.310.2936800.27192137
2.31-2.450.299880.23582129
2.45-2.630.277910.23112181
2.63-2.880.2684840.21012200
2.88-3.280.27981100.18872216
3.28-4.040.2447820.14912137
4.04-80.2343940.15612343
Xplor fileSerial no: 1 / Param file: PARHCSDX.PRO,PARAM11.WAT / Topol file: TOPHCSDX.PRO
Refinement
*PLUS
Lowest resolution: 8 Å / Rfactor Rwork: 0.19
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_improper_angle_d
X-RAY DIFFRACTIONx_improper_angle_deg1.56
LS refinement shell
*PLUS
Rfactor Rfree: 0.343

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