HEADER HYDROLASE 05-DEC-07 2VIV
TITLE FRAGMENT-BASED DISCOVERY OF MEXILETINE DERIVATIVES AS ORALLY
TITLE 2 BIOAVAILABLE INHIBITORS OF UROKINASE-TYPE PLASMINOGEN ACTIVATOR
COMPND MOL_ID: 1;
COMPND 2 MOLECULE: UROKINASE-TYPE PLASMINOGEN ACTIVATOR CHAIN B;
COMPND 3 CHAIN: A;
COMPND 4 FRAGMENT: CATALYTIC DOMAIN, RESIDUES 179-431;
COMPND 5 SYNONYM: UROKINASE-TYPE PLASMINOGEN ACTIVATOR, UPA, U-PLASMINOGEN
COMPND 6 ACTIVATOR;
COMPND 7 EC: 3.4.21.73;
COMPND 8 ENGINEERED: YES;
COMPND 9 MUTATION: YES
SOURCE MOL_ID: 1;
SOURCE 2 ORGANISM_SCIENTIFIC: HOMO SAPIENS;
SOURCE 3 ORGANISM_COMMON: HUMAN;
SOURCE 4 ORGANISM_TAXID: 9606;
SOURCE 5 EXPRESSION_SYSTEM: ESCHERICHIA COLI;
SOURCE 6 EXPRESSION_SYSTEM_TAXID: 562
KEYWDS PLASMINOGEN ACTIVATION, EGF-LIKE DOMAIN, BLOOD COAGULATION,
KEYWDS 2 INHIBITOR, POLYMORPHISM, GLYCOPROTEIN, FIBRINOLYSIS, KRINGLE,
KEYWDS 3 ZYMOGEN, SECRETED, PROTEASE, HYDROLASE, UROKINASE-TYPE PLASMINOGEN
KEYWDS 4 ACTIVATOR, PHARMACEUTICAL, SERINE PROTEASE, PHOSPHORYLATION
EXPDTA X-RAY DIFFRACTION
AUTHOR M.FREDERICKSON,O.CALLAGHAN,G.CHESSARI,M.CONGREVE,S.R.COWAN,
AUTHOR 2 J.E.MATTHEWS,R.MCMENAMIN,D.SMITH,M.VINKOVIC,N.G.WALLIS
REVDAT 4 05-JUL-17 2VIV 1 REMARK
REVDAT 3 24-FEB-09 2VIV 1 VERSN
REVDAT 2 29-JAN-08 2VIV 1 JRNL
REVDAT 1 22-JAN-08 2VIV 0
JRNL AUTH M.FREDERICKSON,O.CALLAGHAN,G.CHESSARI,M.CONGREVE,S.R.COWAN,
JRNL AUTH 2 J.E.MATTHEWS,R.MCMENAMIN,D.SMITH,M.VINKOVIC,N.G.WALLIS
JRNL TITL FRAGMENT-BASED DISCOVERY OF MEXILETINE DERIVATIVES AS ORALLY
JRNL TITL 2 BIOAVAILABLE INHIBITORS OF UROKINASE-TYPE PLASMINOGEN
JRNL TITL 3 ACTIVATOR.
JRNL REF J.MED.CHEM. V. 51 183 2008
JRNL REFN ISSN 0022-2623
JRNL PMID 18163548
JRNL DOI 10.1021/JM701359Z
REMARK 2
REMARK 2 RESOLUTION. 1.72 ANGSTROMS.
REMARK 3
REMARK 3 REFINEMENT.
REMARK 3 PROGRAM : BUSTER-TNT 2.1.1
REMARK 3 AUTHORS : BRICOGNE,BLANC,BRANDL,FLENSBURG,KELLER,
REMARK 3 : PACIOREK,ROVERSI,SMART,VONRHEIN,WOMACK,
REMARK 3 : MATTHEWS,TEN EYCK,TRONRUD
REMARK 3
REMARK 3 DATA USED IN REFINEMENT.
REMARK 3 RESOLUTION RANGE HIGH (ANGSTROMS) : 1.72
REMARK 3 RESOLUTION RANGE LOW (ANGSTROMS) : 34.16
REMARK 3 DATA CUTOFF (SIGMA(F)) : 0.000
REMARK 3 COMPLETENESS FOR RANGE (%) : 82.8
REMARK 3 NUMBER OF REFLECTIONS : 21002
REMARK 3
REMARK 3 FIT TO DATA USED IN REFINEMENT.
REMARK 3 CROSS-VALIDATION METHOD : THROUGHOUT
REMARK 3 FREE R VALUE TEST SET SELECTION : RANDOM
REMARK 3 R VALUE (WORKING + TEST SET) : 0.183
REMARK 3 R VALUE (WORKING SET) : 0.180
REMARK 3 FREE R VALUE : 0.238
REMARK 3 FREE R VALUE TEST SET SIZE (%) : 5.000
REMARK 3 FREE R VALUE TEST SET COUNT : 1044
REMARK 3 ESTIMATED ERROR OF FREE R VALUE : NULL
REMARK 3
REMARK 3 FIT IN THE HIGHEST RESOLUTION BIN.
REMARK 3 TOTAL NUMBER OF BINS USED : NULL
REMARK 3 BIN RESOLUTION RANGE HIGH (ANGSTROMS) : NULL
REMARK 3 BIN RESOLUTION RANGE LOW (ANGSTROMS) : NULL
REMARK 3 BIN COMPLETENESS (WORKING+TEST) (%) : NULL
REMARK 3 REFLECTIONS IN BIN (WORKING + TEST SET) : NULL
REMARK 3 BIN R VALUE (WORKING + TEST SET) : NULL
REMARK 3 REFLECTIONS IN BIN (WORKING SET) : NULL
REMARK 3 BIN R VALUE (WORKING SET) : NULL
REMARK 3 BIN FREE R VALUE : NULL
REMARK 3 BIN FREE R VALUE TEST SET SIZE (%) : NULL
REMARK 3 BIN FREE R VALUE TEST SET COUNT : NULL
REMARK 3 ESTIMATED ERROR OF BIN FREE R VALUE : NULL
REMARK 3
REMARK 3 NUMBER OF NON-HYDROGEN ATOMS USED IN REFINEMENT.
REMARK 3 PROTEIN ATOMS : 1952
REMARK 3 NUCLEIC ACID ATOMS : 0
REMARK 3 HETEROGEN ATOMS : 32
REMARK 3 SOLVENT ATOMS : 224
REMARK 3
REMARK 3 B VALUES.
REMARK 3 FROM WILSON PLOT (A**2) : NULL
REMARK 3 MEAN B VALUE (OVERALL, A**2) : NULL
REMARK 3 OVERALL ANISOTROPIC B VALUE.
REMARK 3 B11 (A**2) : NULL
REMARK 3 B22 (A**2) : NULL
REMARK 3 B33 (A**2) : NULL
REMARK 3 B12 (A**2) : NULL
REMARK 3 B13 (A**2) : NULL
REMARK 3 B23 (A**2) : NULL
REMARK 3
REMARK 3 ESTIMATED COORDINATE ERROR.
REMARK 3 ESD FROM LUZZATI PLOT (A) : NULL
REMARK 3 DPI (BLOW EQ-10) BASED ON R VALUE (A) : NULL
REMARK 3 DPI (BLOW EQ-9) BASED ON FREE R VALUE (A) : NULL
REMARK 3 DPI (CRUICKSHANK) BASED ON R VALUE (A) : NULL
REMARK 3 DPI (CRUICKSHANK) BASED ON FREE R VALUE (A) : NULL
REMARK 3
REMARK 3 REFERENCES: BLOW, D. (2002) ACTA CRYST D58, 792-797
REMARK 3 CRUICKSHANK, D.W.J. (1999) ACTA CRYST D55, 583-601
REMARK 3
REMARK 3 CORRELATION COEFFICIENTS.
REMARK 3 CORRELATION COEFFICIENT FO-FC : NULL
REMARK 3 CORRELATION COEFFICIENT FO-FC FREE : NULL
REMARK 3
REMARK 3 NUMBER OF GEOMETRIC FUNCTION TERMS DEFINED : 15
REMARK 3 TERM COUNT WEIGHT FUNCTION.
REMARK 3 BOND LENGTHS : NULL ; NULL ; NULL
REMARK 3 BOND ANGLES : NULL ; NULL ; NULL
REMARK 3 TORSION ANGLES : NULL ; NULL ; NULL
REMARK 3 TRIGONAL CARBON PLANES : NULL ; NULL ; NULL
REMARK 3 GENERAL PLANES : NULL ; NULL ; NULL
REMARK 3 ISOTROPIC THERMAL FACTORS : NULL ; NULL ; NULL
REMARK 3 BAD NON-BONDED CONTACTS : NULL ; NULL ; NULL
REMARK 3 IMPROPER TORSIONS : NULL ; NULL ; NULL
REMARK 3 PSEUDOROTATION ANGLES : NULL ; NULL ; NULL
REMARK 3 CHIRAL IMPROPER TORSION : NULL ; NULL ; NULL
REMARK 3 SUM OF OCCUPANCIES : NULL ; NULL ; NULL
REMARK 3 UTILITY DISTANCES : NULL ; NULL ; NULL
REMARK 3 UTILITY ANGLES : NULL ; NULL ; NULL
REMARK 3 UTILITY TORSION : NULL ; NULL ; NULL
REMARK 3 IDEAL-DIST CONTACT TERM : NULL ; NULL ; NULL
REMARK 3
REMARK 3 RMS DEVIATIONS FROM IDEAL VALUES.
REMARK 3 BOND LENGTHS (A) : NULL
REMARK 3 BOND ANGLES (DEGREES) : NULL
REMARK 3 PEPTIDE OMEGA TORSION ANGLES (DEGREES) : NULL
REMARK 3 OTHER TORSION ANGLES (DEGREES) : NULL
REMARK 3
REMARK 3 TLS DETAILS
REMARK 3 NUMBER OF TLS GROUPS : NULL
REMARK 3
REMARK 3 OTHER REFINEMENT REMARKS: NULL
REMARK 4
REMARK 4 2VIV COMPLIES WITH FORMAT V. 3.30, 13-JUL-11
REMARK 100
REMARK 100 THIS ENTRY HAS BEEN PROCESSED BY PDBE ON 05-DEC-07.
REMARK 100 THE DEPOSITION ID IS D_1290034674.
REMARK 200
REMARK 200 EXPERIMENTAL DETAILS
REMARK 200 EXPERIMENT TYPE : X-RAY DIFFRACTION
REMARK 200 DATE OF DATA COLLECTION : NULL
REMARK 200 TEMPERATURE (KELVIN) : 93
REMARK 200 PH : 6.6
REMARK 200 NUMBER OF CRYSTALS USED : 1
REMARK 200
REMARK 200 SYNCHROTRON (Y/N) : N
REMARK 200 RADIATION SOURCE : ROTATING ANODE
REMARK 200 BEAMLINE : NULL
REMARK 200 X-RAY GENERATOR MODEL : RIGAKU RUH3R
REMARK 200 MONOCHROMATIC OR LAUE (M/L) : M
REMARK 200 WAVELENGTH OR RANGE (A) : 1.5418
REMARK 200 MONOCHROMATOR : NULL
REMARK 200 OPTICS : OSMIC BLUE CONFOCAL OPTICS
REMARK 200
REMARK 200 DETECTOR TYPE : CCD
REMARK 200 DETECTOR MANUFACTURER : RIGAKU CCD
REMARK 200 INTENSITY-INTEGRATION SOFTWARE : D*TREK
REMARK 200 DATA SCALING SOFTWARE : D*TREK
REMARK 200
REMARK 200 NUMBER OF UNIQUE REFLECTIONS : 21002
REMARK 200 RESOLUTION RANGE HIGH (A) : 1.720
REMARK 200 RESOLUTION RANGE LOW (A) : 34.160
REMARK 200 REJECTION CRITERIA (SIGMA(I)) : 0.000
REMARK 200
REMARK 200 OVERALL.
REMARK 200 COMPLETENESS FOR RANGE (%) : 82.8
REMARK 200 DATA REDUNDANCY : 2.400
REMARK 200 R MERGE (I) : 0.06000
REMARK 200 R SYM (I) : NULL
REMARK 200 <I/SIGMA(I)> FOR THE DATA SET : NULL
REMARK 200
REMARK 200 IN THE HIGHEST RESOLUTION SHELL.
REMARK 200 HIGHEST RESOLUTION SHELL, RANGE HIGH (A) : 1.72
REMARK 200 HIGHEST RESOLUTION SHELL, RANGE LOW (A) : 1.73
REMARK 200 COMPLETENESS FOR SHELL (%) : 22.6
REMARK 200 DATA REDUNDANCY IN SHELL : NULL
REMARK 200 R MERGE FOR SHELL (I) : 0.29000
REMARK 200 R SYM FOR SHELL (I) : NULL
REMARK 200 <I/SIGMA(I)> FOR SHELL : 2.000
REMARK 200
REMARK 200 DIFFRACTION PROTOCOL: SINGLE WAVELENGTH
REMARK 200 METHOD USED TO DETERMINE THE STRUCTURE: OTHER
REMARK 200 SOFTWARE USED: NULL
REMARK 200 STARTING MODEL: NONE
REMARK 200
REMARK 200 REMARK: NONE
REMARK 280
REMARK 280 CRYSTAL
REMARK 280 SOLVENT CONTENT, VS (%): 39.54
REMARK 280 MATTHEWS COEFFICIENT, VM (ANGSTROMS**3/DA): 1.86
REMARK 280
REMARK 280 CRYSTALLIZATION CONDITIONS: PROTEIN WAS CRYSTALLIZED FROM 22-24%
REMARK 280 PEG4000, 0.17M (NH4)2SO4, 15% GLYCEROL, 0.1M NA(CH3COO) PH=4.0;
REMARK 280 THEN SOAKED IN 0.04M COMPOUND, 28% PEG4000, 5% GLYCEROL, 0.29M
REMARK 280 BISTRIS PH=6.6, 0.001M NA(CH3COO), 0.001M (NH4)2SO4, PH 6.6
REMARK 290
REMARK 290 CRYSTALLOGRAPHIC SYMMETRY
REMARK 290 SYMMETRY OPERATORS FOR SPACE GROUP: P 21 21 21
REMARK 290
REMARK 290 SYMOP SYMMETRY
REMARK 290 NNNMMM OPERATOR
REMARK 290 1555 X,Y,Z
REMARK 290 2555 -X+1/2,-Y,Z+1/2
REMARK 290 3555 -X,Y+1/2,-Z+1/2
REMARK 290 4555 X+1/2,-Y+1/2,-Z
REMARK 290
REMARK 290 WHERE NNN -> OPERATOR NUMBER
REMARK 290 MMM -> TRANSLATION VECTOR
REMARK 290
REMARK 290 CRYSTALLOGRAPHIC SYMMETRY TRANSFORMATIONS
REMARK 290 THE FOLLOWING TRANSFORMATIONS OPERATE ON THE ATOM/HETATM
REMARK 290 RECORDS IN THIS ENTRY TO PRODUCE CRYSTALLOGRAPHICALLY
REMARK 290 RELATED MOLECULES.
REMARK 290 SMTRY1 1 1.000000 0.000000 0.000000 0.00000
REMARK 290 SMTRY2 1 0.000000 1.000000 0.000000 0.00000
REMARK 290 SMTRY3 1 0.000000 0.000000 1.000000 0.00000
REMARK 290 SMTRY1 2 -1.000000 0.000000 0.000000 26.16900
REMARK 290 SMTRY2 2 0.000000 -1.000000 0.000000 0.00000
REMARK 290 SMTRY3 2 0.000000 0.000000 1.000000 40.96900
REMARK 290 SMTRY1 3 -1.000000 0.000000 0.000000 0.00000
REMARK 290 SMTRY2 3 0.000000 1.000000 0.000000 27.00050
REMARK 290 SMTRY3 3 0.000000 0.000000 -1.000000 40.96900
REMARK 290 SMTRY1 4 1.000000 0.000000 0.000000 26.16900
REMARK 290 SMTRY2 4 0.000000 -1.000000 0.000000 27.00050
REMARK 290 SMTRY3 4 0.000000 0.000000 -1.000000 0.00000
REMARK 290
REMARK 290 REMARK: NULL
REMARK 300
REMARK 300 BIOMOLECULE: 1
REMARK 300 SEE REMARK 350 FOR THE AUTHOR PROVIDED AND/OR PROGRAM
REMARK 300 GENERATED ASSEMBLY INFORMATION FOR THE STRUCTURE IN
REMARK 300 THIS ENTRY. THE REMARK MAY ALSO PROVIDE INFORMATION ON
REMARK 300 BURIED SURFACE AREA.
REMARK 350
REMARK 350 COORDINATES FOR A COMPLETE MULTIMER REPRESENTING THE KNOWN
REMARK 350 BIOLOGICALLY SIGNIFICANT OLIGOMERIZATION STATE OF THE
REMARK 350 MOLECULE CAN BE GENERATED BY APPLYING BIOMT TRANSFORMATIONS
REMARK 350 GIVEN BELOW. BOTH NON-CRYSTALLOGRAPHIC AND
REMARK 350 CRYSTALLOGRAPHIC OPERATIONS ARE GIVEN.
REMARK 350
REMARK 350 BIOMOLECULE: 1
REMARK 350 AUTHOR DETERMINED BIOLOGICAL UNIT: MONOMERIC
REMARK 350 SOFTWARE DETERMINED QUATERNARY STRUCTURE: MONOMERIC
REMARK 350 SOFTWARE USED: PQS
REMARK 350 APPLY THE FOLLOWING TO CHAINS: A
REMARK 350 BIOMT1 1 1.000000 0.000000 0.000000 0.00000
REMARK 350 BIOMT2 1 0.000000 1.000000 0.000000 0.00000
REMARK 350 BIOMT3 1 0.000000 0.000000 1.000000 0.00000
REMARK 400
REMARK 400 COMPOUND
REMARK 400 ENGINEERED RESIDUE IN CHAIN A, MET 214 TO ILE
REMARK 400 ENGINEERED RESIDUE IN CHAIN A, CYS 299 TO SER
REMARK 465
REMARK 465 MISSING RESIDUES
REMARK 465 THE FOLLOWING RESIDUES WERE NOT LOCATED IN THE
REMARK 465 EXPERIMENT. (M=MODEL NUMBER; RES=RESIDUE NAME; C=CHAIN
REMARK 465 IDENTIFIER; SSSEQ=SEQUENCE NUMBER; I=INSERTION CODE.)
REMARK 465
REMARK 465 M RES C SSSEQI
REMARK 465 ASN A 246
REMARK 465 GLY A 247
REMARK 465 LEU A 248
REMARK 465 ALA A 249
REMARK 465 LEU A 250
REMARK 470
REMARK 470 MISSING ATOM
REMARK 470 THE FOLLOWING RESIDUES HAVE MISSING ATOMS (M=MODEL NUMBER;
REMARK 470 RES=RESIDUE NAME; C=CHAIN IDENTIFIER; SSEQ=SEQUENCE NUMBER;
REMARK 470 I=INSERTION CODE):
REMARK 470 M RES CSSEQI ATOMS
REMARK 470 GLU A 245 CA C O CB CG CD OE1
REMARK 470 GLU A 245 OE2
REMARK 500
REMARK 500 GEOMETRY AND STEREOCHEMISTRY
REMARK 500 SUBTOPIC: CLOSE CONTACTS IN SAME ASYMMETRIC UNIT
REMARK 500
REMARK 500 THE FOLLOWING ATOMS ARE IN CLOSE CONTACT.
REMARK 500
REMARK 500 ATM1 RES C SSEQI ATM2 RES C SSEQI DISTANCE
REMARK 500 O HOH A 2058 O HOH A 2159 1.97
REMARK 500
REMARK 500 REMARK: NULL
REMARK 500
REMARK 500 GEOMETRY AND STEREOCHEMISTRY
REMARK 500 SUBTOPIC: CLOSE CONTACTS
REMARK 500
REMARK 500 THE FOLLOWING ATOMS THAT ARE RELATED BY CRYSTALLOGRAPHIC
REMARK 500 SYMMETRY ARE IN CLOSE CONTACT. AN ATOM LOCATED WITHIN 0.15
REMARK 500 ANGSTROMS OF A SYMMETRY RELATED ATOM IS ASSUMED TO BE ON A
REMARK 500 SPECIAL POSITION AND IS, THEREFORE, LISTED IN REMARK 375
REMARK 500 INSTEAD OF REMARK 500. ATOMS WITH NON-BLANK ALTERNATE
REMARK 500 LOCATION INDICATORS ARE NOT INCLUDED IN THE CALCULATIONS.
REMARK 500
REMARK 500 DISTANCE CUTOFF:
REMARK 500 2.2 ANGSTROMS FOR CONTACTS NOT INVOLVING HYDROGEN ATOMS
REMARK 500 1.6 ANGSTROMS FOR CONTACTS INVOLVING HYDROGEN ATOMS
REMARK 500
REMARK 500 ATM1 RES C SSEQI ATM2 RES C SSEQI SSYMOP DISTANCE
REMARK 500 O HOH A 2143 O HOH A 2154 3645 2.17
REMARK 500
REMARK 500 REMARK: NULL
REMARK 500
REMARK 500 GEOMETRY AND STEREOCHEMISTRY
REMARK 500 SUBTOPIC: TORSION ANGLES
REMARK 500
REMARK 500 TORSION ANGLES OUTSIDE THE EXPECTED RAMACHANDRAN REGIONS:
REMARK 500 (M=MODEL NUMBER; RES=RESIDUE NAME; C=CHAIN IDENTIFIER;
REMARK 500 SSEQ=SEQUENCE NUMBER; I=INSERTION CODE).
REMARK 500
REMARK 500 STANDARD TABLE:
REMARK 500 FORMAT:(10X,I3,1X,A3,1X,A1,I4,A1,4X,F7.2,3X,F7.2)
REMARK 500
REMARK 500 EXPECTED VALUES: GJ KLEYWEGT AND TA JONES (1996). PHI/PSI-
REMARK 500 CHOLOGY: RAMACHANDRAN REVISITED. STRUCTURE 4, 1395 - 1400
REMARK 500
REMARK 500 M RES CSSEQI PSI PHI
REMARK 500 GLN A 27 58.21 -143.68
REMARK 500 VAL A 41 -64.77 -102.40
REMARK 500 SER A 54 -154.03 -149.43
REMARK 500 ASP A 97 -154.18 -100.79
REMARK 500 TYR A 127 29.22 47.70
REMARK 500 TYR A 171 -101.40 -85.12
REMARK 500 SER A 214 -58.43 -128.35
REMARK 500 THR A 242 55.30 -97.58
REMARK 500 LYS A 243 -86.27 -148.46
REMARK 500
REMARK 500 REMARK: NULL
REMARK 700
REMARK 700 SHEET
REMARK 700 DETERMINATION METHOD: DSSP
REMARK 700 THE SHEETS PRESENTED AS "AA" IN EACH CHAIN ON SHEET RECORDS
REMARK 700 BELOW IS ACTUALLY AN 8-STRANDED BARREL THIS IS REPRESENTED BY
REMARK 700 A 9-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS
REMARK 700 ARE IDENTICAL.
REMARK 700 THE SHEETS PRESENTED AS "AB" IN EACH CHAIN ON SHEET RECORDS
REMARK 700 BELOW IS ACTUALLY AN 7-STRANDED BARREL THIS IS REPRESENTED BY
REMARK 700 A 8-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS
REMARK 700 ARE IDENTICAL.
REMARK 800
REMARK 800 SITE
REMARK 800 SITE_IDENTIFIER: AC1
REMARK 800 EVIDENCE_CODE: SOFTWARE
REMARK 800 SITE_DESCRIPTION: BINDING SITE FOR RESIDUE ACT A1246
REMARK 800
REMARK 800 SITE_IDENTIFIER: AC2
REMARK 800 EVIDENCE_CODE: SOFTWARE
REMARK 800 SITE_DESCRIPTION: BINDING SITE FOR RESIDUE VG2 A1247
REMARK 900
REMARK 900 RELATED ENTRIES
REMARK 900 RELATED ID: 1C5X RELATED DB: PDB
REMARK 900 STRUCTURAL BASIS FOR SELECTIVITY OF A SMALL MOLECULE, S1-BINDING,
REMARK 900 SUB- MICROMOLAR INHIBITOR OF UROKINASE TYPE PLASMINOGEN ACTIVATOR
REMARK 900 RELATED ID: 1GJ9 RELATED DB: PDB
REMARK 900 ENGINEERING INHIBITORS HIGHLY SELECTIVE FOR THE S1 SITES OFSER190
REMARK 900 TRYPSIN-LIKE SERINE PROTEASE DRUG TARGETS
REMARK 900 RELATED ID: 1W0Z RELATED DB: PDB
REMARK 900 UPA
REMARK 900 RELATED ID: 1FV9 RELATED DB: PDB
REMARK 900 CRYSTAL STRUCTURE OF HUMAN MICROUROKINASE IN COMPLEX WITH 2-AMINO-5-
REMARK 900 HYDROXY-BENZIMIDAZOLE
REMARK 900 RELATED ID: 1VJA RELATED DB: PDB
REMARK 900 UROKINASE PLASMINOGEN ACTIVATOR B-CHAIN-JT464 COMPLEX
REMARK 900 RELATED ID: 1GJ8 RELATED DB: PDB
REMARK 900 ENGINEERING INHIBITORS HIGHLY SELECTIVE FOR THE S1 SITES OFSER190
REMARK 900 TRYPSIN-LIKE SERINE PROTEASE DRUG TARGETS
REMARK 900 RELATED ID: 1W11 RELATED DB: PDB
REMARK 900 UPA
REMARK 900 RELATED ID: 1SQO RELATED DB: PDB
REMARK 900 SUBSTITUTED 2-NAPHTHAMIDINE INHIBITORS OF UROKINASE
REMARK 900 RELATED ID: 1GJD RELATED DB: PDB
REMARK 900 ENGINEERING INHIBITORS HIGHLY SELECTIVE FOR THE S1 SITES OFSER190
REMARK 900 TRYPSIN-LIKE SERINE PROTEASE DRUG TARGETS
REMARK 900 RELATED ID: 1W10 RELATED DB: PDB
REMARK 900 UPA
REMARK 900 RELATED ID: 1OWK RELATED DB: PDB
REMARK 900 SUBSTITUTED 2-NAPHTHAMIDINE INHIBITORS OF UROKINASE
REMARK 900 RELATED ID: 1W12 RELATED DB: PDB
REMARK 900 UPA
REMARK 900 RELATED ID: 1GI9 RELATED DB: PDB
REMARK 900 A NOVEL SERINE PROTEASE INHIBITION MOTIF INVOLVING A MULTI-CENTERED
REMARK 900 SHORT HYDROGEN BONDING NETWORK AT THE ACTIVE SITE
REMARK 900 RELATED ID: 1O5A RELATED DB: PDB
REMARK 900 DISSECTING AND DESIGNING INHIBITOR SELECTIVITY DETERMINANTSAT THE
REMARK 900 S1 SITE USING AN ARTIFICIAL ALA190 PROTEASE (ALA190UPA)
REMARK 900 RELATED ID: 1C5Z RELATED DB: PDB
REMARK 900 STRUCTURAL BASIS FOR SELECTIVITY OF A SMALL MOLECULE, S1-BINDING,
REMARK 900 SUB- MICROMOLAR INHIBITOR OF UROKINASE TYPE PLASMINOGEN ACTIVATOR
REMARK 900 RELATED ID: 1OWJ RELATED DB: PDB
REMARK 900 SUBSTITUTED 2-NAPHTHAMIDINE INHIBITORS OF UROKINASE
REMARK 900 RELATED ID: 1GI7 RELATED DB: PDB
REMARK 900 A NOVEL SERINE PROTEASE INHIBITION MOTIF INVOLVING A MULTI-CENTERED
REMARK 900 SHORT HYDROGEN BONDING NETWORK AT THE ACTIVE SITE
REMARK 900 RELATED ID: 1O5B RELATED DB: PDB
REMARK 900 DISSECTING AND DESIGNING INHIBITOR SELECTIVITY DETERMINANTSAT THE
REMARK 900 S1 SITE USING AN ARTIFICIAL ALA190 PROTEASE (ALA190UPA)
REMARK 900 RELATED ID: 1GJC RELATED DB: PDB
REMARK 900 ENGINEERING INHIBITORS HIGHLY SELECTIVE FOR THE S1 SITES OFSER190
REMARK 900 TRYPSIN-LIKE SERINE PROTEASE DRUG TARGETS
REMARK 900 RELATED ID: 1SC8 RELATED DB: PDB
REMARK 900 UROKINASE PLASMINOGEN ACTIVATOR B-CHAIN-J435 COMPLEX
REMARK 900 RELATED ID: 1GJA RELATED DB: PDB
REMARK 900 ENGINEERING INHIBITORS HIGHLY SELECTIVE FOR THE S1 SITES OFSER190
REMARK 900 TRYPSIN-LIKE SERINE PROTEASE DRUG TARGETS
REMARK 900 RELATED ID: 1O3P RELATED DB: PDB
REMARK 900 ELABORATE MANIFOLD OF SHORT HYDROGEN BOND ARRAYS MEDIATINGBINDING
REMARK 900 OF ACTIVE SITE- DIRECTED SERINE PROTEASE INHIBITORS
REMARK 900 RELATED ID: 1OWE RELATED DB: PDB
REMARK 900 SUBSTITUTED 2-NAPHTHAMIDINE INHIBITORS OF UROKINASE
REMARK 900 RELATED ID: 1SQA RELATED DB: PDB
REMARK 900 SUBSTITUTED 2-NAPHTHAMIDINE INHIBITORS OF UROKINASE
REMARK 900 RELATED ID: 1GJB RELATED DB: PDB
REMARK 900 ENGINEERING INHIBITORS HIGHLY SELECTIVE FOR THE S1 SITES OFSER190
REMARK 900 TRYPSIN-LIKE SERINE PROTEASE DRUG TARGETS
REMARK 900 RELATED ID: 1F92 RELATED DB: PDB
REMARK 900 UROKINASE PLASMINOGEN ACTIVATOR B CHAIN-UKI- 1D COMPLEX
REMARK 900 RELATED ID: 1OWI RELATED DB: PDB
REMARK 900 SUBSTITUTED 2-NAPHTHAMIDINE INHIBITORS OF UROKINASE
REMARK 900 RELATED ID: 1KDU RELATED DB: PDB
REMARK 900 PLASMINOGEN ACTIVATOR (UROKINASE-TYPE, KRINGLE DOMAIN) (U-PA K)
REMARK 900 (NMR, MINIMIZED AVERAGE STRUCTURE)
REMARK 900 RELATED ID: 1SQT RELATED DB: PDB
REMARK 900 SUBSTITUTED 2-NAPHTHAMIDINE INHIBITORS OF UROKINASE
REMARK 900 RELATED ID: 1F5L RELATED DB: PDB
REMARK 900 UROKINASE PLASMINOGEN ACTIVATOR B-CHAIN- AMILORIDE COMPLEX
REMARK 900 RELATED ID: 1OWD RELATED DB: PDB
REMARK 900 SUBSTITUTED 2-NAPHTHAMIDINE INHIBITORS OF UROKINASE
REMARK 900 RELATED ID: 1EJN RELATED DB: PDB
REMARK 900 UROKINASE PLASMINOGEN ACTIVATOR B-CHAIN INHIBITOR COMPLEX
REMARK 900 RELATED ID: 1LMW RELATED DB: PDB
REMARK 900 LMW U-PA STRUCTURE COMPLEXED WITH EGRCMK ( GLU-GLY-ARG CHLOROMETHYL
REMARK 900 KETONE)
REMARK 900 RELATED ID: 1U6Q RELATED DB: PDB
REMARK 900 SUBSTITUTED 2-NAPHTHAMADINE INHIBITORS OF UROKINASE
REMARK 900 RELATED ID: 1GI8 RELATED DB: PDB
REMARK 900 A NOVEL SERINE PROTEASE INHIBITION MOTIF INVOLVING A MULTI-CENTERED
REMARK 900 SHORT HYDROGEN BONDING NETWORK AT THE ACTIVE SITE
REMARK 900 RELATED ID: 2JDE RELATED DB: PDB
REMARK 900 UROKINASE-TYPE PLASMINOGEN ACTIVATOR INHIBITOR COMPLEX WITHA 1-(7-
REMARK 900 SULPHOAMIDOISOQUINOLINYL) GUANIDINE
REMARK 900 RELATED ID: 1C5Y RELATED DB: PDB
REMARK 900 STRUCTURAL BASIS FOR SELECTIVITY OF A SMALL MOLECULE, S1-BINDING,
REMARK 900 SUB- MICROMOLAR INHIBITOR OF UROKINASE TYPE PLASMINOGEN ACTIVATOR
REMARK 900 RELATED ID: 1W14 RELATED DB: PDB
REMARK 900 UPA
REMARK 900 RELATED ID: 1VJ9 RELATED DB: PDB
REMARK 900 UROKINASE PLASMINOGEN ACTIVATOR B-CHAIN-JT464 COMPLEX
REMARK 900 RELATED ID: 1W13 RELATED DB: PDB
REMARK 900 UPA
REMARK 900 RELATED ID: 1GJ7 RELATED DB: PDB
REMARK 900 ENGINEERING INHIBITORS HIGHLY SELECTIVE FOR THE S1 SITES OFSER190
REMARK 900 TRYPSIN-LIKE SERINE PROTEASE DRUG TARGETS
REMARK 900 RELATED ID: 1C5W RELATED DB: PDB
REMARK 900 STRUCTURAL BASIS FOR SELECTIVITY OF A SMALL MOLECULE, S1-BINDING,
REMARK 900 SUB- MICROMOLAR INHIBITOR OF UROKINASE TYPE PLASMINOGEN ACTIVATOR
REMARK 900 RELATED ID: 1OWH RELATED DB: PDB
REMARK 900 SUBSTITUTED 2-NAPHTHAMIDINE INHIBITORS OF UROKINASE
REMARK 900 RELATED ID: 1O5C RELATED DB: PDB
REMARK 900 DISSECTING AND DESIGNING INHIBITOR SELECTIVITY DETERMINANTSAT THE
REMARK 900 S1 SITE USING AN ARTIFICIAL ALA190 PROTEASE (ALA190UPA)
REMARK 900 RELATED ID: 2VIW RELATED DB: PDB
REMARK 900 FRAGMENT-BASED DISCOVERY OF MEXILETINE DERIVATIVES AS ORALLY
REMARK 900 BIOAVAILABLE INHIBITORS OF UROKINASE-TYPE PLASMINOGEN ACTIV
REMARK 900 RELATED ID: 2VIQ RELATED DB: PDB
REMARK 900 FRAGMENT-BASED DISCOVERY OF MEXILETINE DERIVATIVES AS ORALLY
REMARK 900 BIOAVAILABLE INHIBITORS OF UROKINASE-TYPE PLASMINOGEN ACTIVATOR
REMARK 900 RELATED ID: 2VIN RELATED DB: PDB
REMARK 900 FRAGMENT-BASED DISCOVERY OF MEXILETINE DERIVATIVES AS ORALLY
REMARK 900 BIOAVAILABLE INHIBITORS OF UROKINASE-TYPE PLASMINOGEN ACTIVATOR
REMARK 900 RELATED ID: 2VIO RELATED DB: PDB
REMARK 900 FRAGMENT-BASED DISCOVERY OF MEXILETINE DERIVATIVES AS ORALLY
REMARK 900 BIOAVAILABLE INHIBITORS OF UROKINASE-TYPE PLASMINOGEN ACTIVATOR
REMARK 900 RELATED ID: 2VIP RELATED DB: PDB
REMARK 900 FRAGMENT-BASED DISCOVERY OF MEXILETINE DERIVATIVES AS ORALLY
REMARK 900 BIOAVAILABLE INHIBITORS OF UROKINASE-TYPE PLASMINOGEN ACTIVATOR
DBREF 2VIV A 16 250 UNP P00749 UROK_HUMAN 179 431
SEQADV 2VIV ILE A 47 UNP P00749 MET 214 ENGINEERED MUTATION
SEQADV 2VIV SER A 122 UNP P00749 CYS 299 ENGINEERED MUTATION
SEQRES 1 A 253 ILE ILE GLY GLY GLU PHE THR THR ILE GLU ASN GLN PRO
SEQRES 2 A 253 TRP PHE ALA ALA ILE TYR ARG ARG HIS ARG GLY GLY SER
SEQRES 3 A 253 VAL THR TYR VAL CYS GLY GLY SER LEU ILE SER PRO CYS
SEQRES 4 A 253 TRP VAL ILE SER ALA THR HIS CYS PHE ILE ASP TYR PRO
SEQRES 5 A 253 LYS LYS GLU ASP TYR ILE VAL TYR LEU GLY ARG SER ARG
SEQRES 6 A 253 LEU ASN SER ASN THR GLN GLY GLU MET LYS PHE GLU VAL
SEQRES 7 A 253 GLU ASN LEU ILE LEU HIS LYS ASP TYR SER ALA ASP THR
SEQRES 8 A 253 LEU ALA HIS HIS ASN ASP ILE ALA LEU LEU LYS ILE ARG
SEQRES 9 A 253 SER LYS GLU GLY ARG CYS ALA GLN PRO SER ARG THR ILE
SEQRES 10 A 253 GLN THR ILE SER LEU PRO SER MET TYR ASN ASP PRO GLN
SEQRES 11 A 253 PHE GLY THR SER CYS GLU ILE THR GLY PHE GLY LYS GLU
SEQRES 12 A 253 ASN SER THR ASP TYR LEU TYR PRO GLU GLN LEU LYS MET
SEQRES 13 A 253 THR VAL VAL LYS LEU ILE SER HIS ARG GLU CYS GLN GLN
SEQRES 14 A 253 PRO HIS TYR TYR GLY SER GLU VAL THR THR LYS MET LEU
SEQRES 15 A 253 CYS ALA ALA ASP PRO GLN TRP LYS THR ASP SER CYS GLN
SEQRES 16 A 253 GLY ASP SER GLY GLY PRO LEU VAL CYS SER LEU GLN GLY
SEQRES 17 A 253 ARG MET THR LEU THR GLY ILE VAL SER TRP GLY ARG GLY
SEQRES 18 A 253 CYS ALA LEU LYS ASP LYS PRO GLY VAL TYR THR ARG VAL
SEQRES 19 A 253 SER HIS PHE LEU PRO TRP ILE ARG SER HIS THR LYS GLU
SEQRES 20 A 253 GLU ASN GLY LEU ALA LEU
HET ACT A1246 4
HET VG2 A1247 28
HETNAM ACT ACETATE ION
HETNAM VG2 4-(2-AMINOETHOXY)-N-(3-CHLORO-5-PIPERIDIN-1-YLPHENYL)-
HETNAM 2 VG2 3,5-DIMETHYLBENZAMIDE
FORMUL 2 ACT C2 H3 O2 1-
FORMUL 3 VG2 C22 H28 CL N3 O2
FORMUL 4 HOH *224(H2 O)
HELIX 1 1 THR A 23 GLN A 27 5 5
HELIX 2 2 ALA A 55 PHE A 59 5 5
HELIX 3 3 LYS A 61 GLU A 62A 5 3
HELIX 4 4 SER A 164 GLN A 169 1 6
HELIX 5 5 TYR A 172 VAL A 176 5 5
HELIX 6 6 PHE A 234 THR A 242 1 9
SHEET 1 AA 9 GLU A 20 PHE A 21 0
SHEET 2 AA 9 LYS A 156 ILE A 163 -1 O MET A 157 N GLU A 20
SHEET 3 AA 9 MET A 180 ALA A 184 -1 O CYS A 182 N ILE A 163
SHEET 4 AA 9 GLY A 226 ARG A 230 -1 O GLY A 226 N ALA A 183
SHEET 5 AA 9 ARG A 206 TRP A 215 -1 O ILE A 212 N THR A 229
SHEET 6 AA 9 PRO A 198 LEU A 203 -1 O LEU A 199 N GLY A 211
SHEET 7 AA 9 SER A 135 GLY A 140 -1 O GLU A 137 N VAL A 200
SHEET 8 AA 9 LYS A 156 ILE A 163 1 O LYS A 156 N GLY A 140
SHEET 9 AA 9 GLU A 20 PHE A 21 -1 O GLU A 20 N MET A 157
SHEET 1 AB 8 PHE A 30 ARG A 36 0
SHEET 2 AB 8 VAL A 38 SER A 48 -1 O THR A 39 N ARG A 35
SHEET 3 AB 8 TRP A 51 SER A 54 -1 O TRP A 51 N ILE A 47
SHEET 4 AB 8 ALA A 104 ARG A 109 -1 O ALA A 104 N SER A 54
SHEET 5 AB 8 MET A 81 LEU A 90 -1 O GLU A 84 N ARG A 109
SHEET 6 AB 8 TYR A 64 LEU A 68 -1 O TYR A 64 N VAL A 85
SHEET 7 AB 8 PHE A 30 ARG A 36 -1 O ALA A 32 N TYR A 67
SHEET 8 AB 8 PHE A 30 ARG A 36 0
SHEET 1 AC 2 SER A 95 ALA A 96 0
SHEET 2 AC 2 HIS A 99 HIS A 100 -1 O HIS A 100 N SER A 95
SSBOND 1 CYS A 42 CYS A 58 1555 1555 2.03
SSBOND 2 CYS A 50 CYS A 111 1555 1555 2.02
SSBOND 3 CYS A 136 CYS A 201 1555 1555 2.03
SSBOND 4 CYS A 168 CYS A 182 1555 1555 2.03
SSBOND 5 CYS A 191 CYS A 220 1555 1555 2.03
SITE 1 AC1 5 HIS A 57 GLY A 193 SER A 195 VG2 A1247
SITE 2 AC1 5 HOH A2223
SITE 1 AC2 17 GLU A 20 HIS A 57 HIS A 99 ASP A 189
SITE 2 AC2 17 SER A 190 CYS A 191 GLN A 192 SER A 195
SITE 3 AC2 17 VAL A 213 TRP A 215 GLY A 216 GLY A 219
SITE 4 AC2 17 CYS A 220 ACT A1246 HOH A2215 HOH A2223
SITE 5 AC2 17 HOH A2224
CRYST1 52.338 54.001 81.938 90.00 90.00 90.00 P 21 21 21 4
ORIGX1 1.000000 0.000000 0.000000 0.00000
ORIGX2 0.000000 1.000000 0.000000 0.00000
ORIGX3 0.000000 0.000000 1.000000 0.00000
SCALE1 0.019107 0.000000 0.000000 0.00000
SCALE2 0.000000 0.018518 0.000000 0.00000
SCALE3 0.000000 0.000000 0.012204 0.00000
(ATOM LINES ARE NOT SHOWN.)
END
