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- PDB-4bvw: Identification of small molecule inhibitors selective for apo(a) ... -

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Basic information

Entry
Database: PDB / ID: 4bvw
TitleIdentification of small molecule inhibitors selective for apo(a) kringles KIV-7, KIV-10 and KV.
ComponentsAPOLIPOPROTEIN(A)
KeywordsHYDROLASE / CARDIOVASCULAR DISEASE / DRUG DISCOVERY / OPTICAL BIOSENSORS
Function / homology
Function and homology information


plasma lipoprotein particle / LDL remodeling / blood circulation / endopeptidase inhibitor activity / lipid transport / fibronectin binding / Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases / apolipoprotein binding / lipid metabolic process / heparin binding ...plasma lipoprotein particle / LDL remodeling / blood circulation / endopeptidase inhibitor activity / lipid transport / fibronectin binding / Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases / apolipoprotein binding / lipid metabolic process / heparin binding / serine-type endopeptidase activity / proteolysis / extracellular region
Similarity search - Function
Plasminogen Kringle 4 / Plasminogen Kringle 4 / : / Kringle domain / Kringle / Kringle, conserved site / Kringle superfamily / Kringle domain signature. / Kringle domain profile. / Kringle domain ...Plasminogen Kringle 4 / Plasminogen Kringle 4 / : / Kringle domain / Kringle / Kringle, conserved site / Kringle superfamily / Kringle domain signature. / Kringle domain profile. / Kringle domain / 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 / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid / Apolipoprotein(a)
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsSandmark, J. / Althage, M. / Andersson, G.M.K. / Antonsson, T. / Blaho, S. / Bodin, C. / Bostrom, J. / Chen, Y. / Dahlen, A. / Eriksson, P.O. ...Sandmark, J. / Althage, M. / Andersson, G.M.K. / Antonsson, T. / Blaho, S. / Bodin, C. / Bostrom, J. / Chen, Y. / Dahlen, A. / Eriksson, P.O. / Evertsson, E. / Fex, T. / Fjellstrom, O. / Gustafsson, D. / Hallberg, C. / Hicks, R. / Jarkvist, E. / Johansson, C. / Kalies, I. / Kang, D. / Svalstedt Karlsson, B. / Kartberg, F. / Legnehed, A. / Lindqvist, A.M. / Martinsson, S.A. / Moberg, A. / Petersson, A.U. / Ridderstrom, M. / Thelin, A. / Tigerstrom, A. / Vinblad, J. / Xu, B. / Knecht, W.
CitationJournal: To be Published
Title: Small Molecules Used to Decipher the Pathophysiological Roles of the Kringle Domains Kiv-7, - 10 and Kv of Apolipoprotein(A)
Authors: Sandmark, J. / Althage, M. / Andersson, G.M.K. / Antonsson, T. / Blaho, S. / Bodin, C. / Bostrom, J. / Chen, Y. / Dahlen, A. / Eriksson, P.O. / Evertsson, E. / Fex, T. / Fjellstrom, O. / ...Authors: Sandmark, J. / Althage, M. / Andersson, G.M.K. / Antonsson, T. / Blaho, S. / Bodin, C. / Bostrom, J. / Chen, Y. / Dahlen, A. / Eriksson, P.O. / Evertsson, E. / Fex, T. / Fjellstrom, O. / Gustafsson, D. / Hallberg, C. / Hicks, R. / Jarkvist, E. / Johansson, C. / Kalies, I. / Kang, D. / Svalstedt Karlsson, B. / Kartberg, F. / Legnehed, A. / Lindqvist, A.M. / Martinsson, S.A. / Moberg, A. / Petersson, A.U. / Ridderstrom, M. / Thelin, A. / Tigerstrom, A. / Vinblad, J. / Xu, B. / Knecht, W.
History
DepositionJun 28, 2013Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 16, 2014Provider: repository / Type: Initial release
Revision 1.1Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / 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 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.2Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: APOLIPOPROTEIN(A)
B: APOLIPOPROTEIN(A)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,1519
Polymers22,5932
Non-polymers5587
Water2,018112
1
A: APOLIPOPROTEIN(A)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,5454
Polymers11,2961
Non-polymers2483
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: APOLIPOPROTEIN(A)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,6075
Polymers11,2961
Non-polymers3104
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)34.554, 34.129, 67.241
Angle α, β, γ (deg.)90.00, 92.76, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS oper: (Code: given
Matrix: (-1, 0.005047, 0.007257), (0.005044, 1, -0.000342), (-0.007258, -0.000305, -1)
Vector: 77.62, 10.55, 168.3)

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Components

#1: Protein APOLIPOPROTEIN(A) / APO(A) / LP(A) / APOLIPOPROTEIN A


Mass: 11296.453 Da / Num. of mol.: 2 / Fragment: KRINGLE DOMAIN IV-7, RESIDUES 3781-3859 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PPICZALPHAC / Production host: KOMAGATAELLA PASTORIS (fungus) / Strain (production host): X-33
References: UniProt: P08519, Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases
#2: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-HKY / 1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid


Mass: 177.200 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H11NO2
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 112 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY
Sequence detailsN74A MUTATION. N-TERMINAL EXTENSION, PART OF THE ALPHA MATING FACTOR FROM THE EXPRESSION VECTOR, ...N74A MUTATION. N-TERMINAL EXTENSION, PART OF THE ALPHA MATING FACTOR FROM THE EXPRESSION VECTOR, NOT VISIBLE IN ELECTRON DENSITY.

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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: 2.3 Å3/Da / Density % sol: 46 % / Description: NONE
Crystal growDetails: 19% PEG 6000, 0.1 M NAOAC, 12% ETHYLENE GLYCOL, 1M LISO4

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.873
DetectorType: ADSC CCD / Detector: CCD / Date: Jun 20, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.873 Å / Relative weight: 1
ReflectionResolution: 2→30 Å / Num. obs: 10414 / % possible obs: 96.1 % / Observed criterion σ(I): 2 / Redundancy: 3.1 % / Rmerge(I) obs: 0.13 / Net I/σ(I): 6.6
Reflection shellResolution: 2→2.05 Å / Redundancy: 3 % / Rmerge(I) obs: 0.53 / Mean I/σ(I) obs: 1.9 / % possible all: 94.6

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Processing

Software
NameVersionClassification
REFMAC5.7.0029refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1I71

1i71


Resolution: 2→24.68 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.919 / Cross valid method: THROUGHOUT / ESU R: 0.26 / ESU R Free: 0.203 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. THE N-TERMINAL EXTENSION ORIGINATING FROM THE EXPRESSION VECTOR WAS NOT MODELLED.
RfactorNum. reflection% reflectionSelection details
Rfree0.24412 467 4.8 %RANDOM
Rwork0.19155 ---
obs0.19399 9329 90.54 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 17.229 Å2
Baniso -1Baniso -2Baniso -3
1--1.47 Å20 Å2-0.4 Å2
2---0 Å20 Å2
3---1.48 Å2
Refinement stepCycle: LAST / Resolution: 2→24.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1296 0 34 112 1442
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0191397
X-RAY DIFFRACTIONr_bond_other_d00.021120
X-RAY DIFFRACTIONr_angle_refined_deg1.2361.9271910
X-RAY DIFFRACTIONr_angle_other_deg3.7353.0092562
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6755158
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.04221.94472
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.81415189
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.6511514
X-RAY DIFFRACTIONr_chiral_restr0.0740.2177
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0211645
X-RAY DIFFRACTIONr_gen_planes_other0.0070.02369
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.227 25 -
Rwork0.285 620 -
obs--82.8 %

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