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- PDB-6t8u: Complement factor B in complex with 5-Bromo-3-chloro-N-(4,5-dihyd... -

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Basic information

Entry
Database: PDB / ID: 6t8u
TitleComplement factor B in complex with 5-Bromo-3-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-7-methyl-1H-indol-4-amine
ComponentsComplement factor B
KeywordsHYDROLASE / Complement immune / inhibitor
Function / homology
Function and homology information


alternative-complement-pathway C3/C5 convertase / complement binding / Alternative complement activation / Activation of C3 and C5 / complement activation / complement activation, alternative pathway / Regulation of Complement cascade / response to bacterium / blood microparticle / serine-type endopeptidase activity ...alternative-complement-pathway C3/C5 convertase / complement binding / Alternative complement activation / Activation of C3 and C5 / complement activation / complement activation, alternative pathway / Regulation of Complement cascade / response to bacterium / blood microparticle / serine-type endopeptidase activity / proteolysis / extracellular space / extracellular exosome / extracellular region / plasma membrane
Similarity search - Function
Complement factor B / Complement B/C2 / Sushi repeat (SCR repeat) / Domain abundant in complement control proteins; SUSHI repeat; short complement-like repeat (SCR) / von Willebrand factor type A domain / Sushi/SCR/CCP domain / Sushi/CCP/SCR domain profile. / Sushi/SCR/CCP superfamily / VWFA domain profile. / von Willebrand factor (vWF) type A domain ...Complement factor B / Complement B/C2 / Sushi repeat (SCR repeat) / Domain abundant in complement control proteins; SUSHI repeat; short complement-like repeat (SCR) / von Willebrand factor type A domain / Sushi/SCR/CCP domain / Sushi/CCP/SCR domain profile. / Sushi/SCR/CCP superfamily / VWFA domain profile. / von Willebrand factor (vWF) type A domain / von Willebrand factor, type A / von Willebrand factor A-like domain superfamily / 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
Similarity search - Domain/homology
Chem-MVZ / Complement factor B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.84 Å
AuthorsMainolfi, N. / Ehara, T. / Karki, R.G. / Anderson, K. / Mac Sweeney, A. / Wiesmann, C. / Adams, C. / Liao, S.-M. / Argikar, U.A. / Jendza, K. ...Mainolfi, N. / Ehara, T. / Karki, R.G. / Anderson, K. / Mac Sweeney, A. / Wiesmann, C. / Adams, C. / Liao, S.-M. / Argikar, U.A. / Jendza, K. / Zhang, C. / Powers, J. / Klosowski, D.W. / Crowley, M. / Kawanami, T. / Ding, J. / April, M. / Forster, C. / Serrano-Wu, M. / Capparelli, M. / Ramqaj, R. / Solovay, C. / Cumin, F. / Smith, T.M. / Ferrara, L. / Lee, W. / Long, D. / Prentiss, M. / De Erkenez, A. / Yang, L. / Fang, L. / Sellner, H. / Sirockin, F. / Valeur, E. / Erbel, P. / Ramage, P. / Gerhartz, B. / Schubart, A. / Flohr, S. / Gradoux, N. / Feifel, R. / Vogg, B. / Maibaum, J. / Eder, J. / Sedrani, R. / Harrison, R.A. / Mogi, M. / Jaffee, B.D. / Adams, C.M.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery of 4-((2S,4S)-4-Ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic Acid (LNP023), a Factor B Inhibitor Specifically Designed To Be Applicable to Treating a ...Title: Discovery of 4-((2S,4S)-4-Ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic Acid (LNP023), a Factor B Inhibitor Specifically Designed To Be Applicable to Treating a Diverse Array of Complement Mediated Diseases.
Authors: Mainolfi, N. / Ehara, T. / Karki, R.G. / Anderson, K. / Mac Sweeney, A. / Liao, S.M. / Argikar, U.A. / Jendza, K. / Zhang, C. / Powers, J. / Klosowski, D.W. / Crowley, M. / Kawanami, T. / ...Authors: Mainolfi, N. / Ehara, T. / Karki, R.G. / Anderson, K. / Mac Sweeney, A. / Liao, S.M. / Argikar, U.A. / Jendza, K. / Zhang, C. / Powers, J. / Klosowski, D.W. / Crowley, M. / Kawanami, T. / Ding, J. / April, M. / Forster, C. / Serrano-Wu, M. / Capparelli, M. / Ramqaj, R. / Solovay, C. / Cumin, F. / Smith, T.M. / Ferrara, L. / Lee, W. / Long, D. / Prentiss, M. / De Erkenez, A. / Yang, L. / Liu, F. / Sellner, H. / Sirockin, F. / Valeur, E. / Erbel, P. / Ostermeier, D. / Ramage, P. / Gerhartz, B. / Schubart, A. / Flohr, S. / Gradoux, N. / Feifel, R. / Vogg, B. / Wiesmann, C. / Maibaum, J. / Eder, J. / Sedrani, R. / Harrison, R.A. / Mogi, M. / Jaffee, B.D. / Adams, C.M.
History
DepositionOct 25, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 4, 2020Provider: repository / Type: Initial release
Revision 1.1Jul 1, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Jan 24, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: atom_type / chem_comp_atom ...atom_type / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z ..._atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Nov 13, 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
AAA: Complement factor B
BBB: Complement factor B
CCC: Complement factor B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,61314
Polymers98,8683
Non-polymers1,74511
Water81145
1
AAA: Complement factor B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,5705
Polymers32,9561
Non-polymers6144
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
BBB: Complement factor B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,5705
Polymers32,9561
Non-polymers6144
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
CCC: Complement factor B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,4744
Polymers32,9561
Non-polymers5183
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)91.926, 91.926, 260.415
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11Chains A B
21Chains A C
31Chains B C

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Components

#1: Protein Complement factor B / C3/C5 convertase / Glycine-rich beta glycoprotein / GBG / PBF2 / Properdin factor B


Mass: 32955.883 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CFB, BF, BFD / Production host: Drosophila melanogaster (fruit fly)
References: UniProt: P00751, alternative-complement-pathway C3/C5 convertase
#2: Chemical ChemComp-MVZ / 5-bromanyl-3-chloranyl-~{N}-(1~{H}-imidazol-2-yl)-7-methyl-1~{H}-indol-4-amine


Mass: 325.592 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C12H10BrClN4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 45 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
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: 2.78 Å3/Da / Density % sol: 55.79 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop
Details: 2.4M AMMONIUM SULPHATE, 0.1 M SODIUM ACETATE PH 4.6

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Aug 10, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.84→91.91 Å / Num. obs: 27309 / % possible obs: 100 % / Redundancy: 13 % / Rmerge(I) obs: 0.146 / Rrim(I) all: 0.152 / Net I/σ(I): 20.75
Reflection shellResolution: 2.84→2.93 Å / Rmerge(I) obs: 0.5 / Mean I/σ(I) obs: 7.39 / Num. unique obs: 2383 / Rrim(I) all: 0.52 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0257refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1DLE

1dle


Resolution: 2.84→86.684 Å / Cor.coef. Fo:Fc: 0.916 / Cor.coef. Fo:Fc free: 0.874 / SU B: 12.723 / SU ML: 0.248 / Cross valid method: FREE R-VALUE / ESU R Free: 0.343
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2389 1366 5.002 %
Rwork0.1976 --
all0.2 --
obs-27308 99.985 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 25.84 Å2
Baniso -1Baniso -2Baniso -3
1-0.018 Å2-0 Å2-0 Å2
2--0.018 Å2-0 Å2
3----0.036 Å2
Refinement stepCycle: LAST / Resolution: 2.84→86.684 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6284 0 94 45 6423
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0126524
X-RAY DIFFRACTIONr_angle_refined_deg1.7141.6538844
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6465787
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.15122.862311
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.423151120
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.7971533
X-RAY DIFFRACTIONr_chiral_restr0.1270.2826
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.024900
X-RAY DIFFRACTIONr_nbd_refined0.2190.22513
X-RAY DIFFRACTIONr_nbtor_refined0.320.24287
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1330.2182
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1770.258
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2140.27
X-RAY DIFFRACTIONr_mcbond_it2.8632.3843190
X-RAY DIFFRACTIONr_mcangle_it4.7683.5533963
X-RAY DIFFRACTIONr_scbond_it3.932.7623332
X-RAY DIFFRACTIONr_scangle_it6.1243.9874880
X-RAY DIFFRACTIONr_lrange_it8.9430.5879131
X-RAY DIFFRACTIONr_ncsr_local_group_10.0890.058081
X-RAY DIFFRACTIONr_ncsr_local_group_20.0890.058089
X-RAY DIFFRACTIONr_ncsr_local_group_30.0850.058154
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
2.84-2.9140.354980.26918680.27319660.8430.8931000.229
2.914-2.9930.363970.23318240.23919210.8460.9011000.199
2.993-3.080.323930.22617790.2318720.8690.9111000.197
3.08-3.1750.273920.21117400.21418320.9130.9261000.188
3.175-3.2790.228880.1916770.19217650.9310.9431000.167
3.279-3.3940.279850.21116250.21517100.90.9241000.19
3.394-3.5220.22840.19915770.216610.9270.9381000.182
3.522-3.6650.255790.20515160.20815960.9220.93399.93730.188
3.665-3.8280.212780.18614830.18715610.9470.9491000.172
3.828-4.0140.239720.18113710.18414430.9280.951000.167
4.014-4.2310.211710.15413390.15614110.9540.96799.92910.144
4.231-4.4870.19670.15212820.15413490.9580.9671000.143
4.487-4.7960.181630.1611960.16112590.9610.9621000.148
4.796-5.1790.235600.18711240.18911840.9340.9521000.175
5.179-5.6710.209540.2110340.2110880.9430.9421000.194
5.671-6.3370.269500.2239470.2259970.9260.9321000.205
6.337-7.3110.19450.1958550.1959010.9520.95899.8890.185
7.311-8.9380.168390.1847400.1837790.9650.9631000.178
8.938-12.5740.181310.1965890.1956200.9680.9591000.199
12.574-86.6840.325200.3493760.3483970.8960.89599.74810.348

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