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- PDB-6t8w: Complement factor B in complex with (-)-4-(1-((5,7-Dimethyl-1H-in... -

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Basic information

Entry
Database: PDB / ID: 6t8w
TitleComplement factor B in complex with (-)-4-(1-((5,7-Dimethyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid
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-MVW / Complement factor B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsMainolfi, N. / Ehara, T. / Karki, R.G. / Anderson, K. / Sweeney, A.M. / Wiesmann, C. / Adams, C. / Mainolfi, N. / Liao, S.M. / Argikar, U.A. ...Mainolfi, N. / Ehara, T. / Karki, R.G. / Anderson, K. / Sweeney, A.M. / Wiesmann, C. / Adams, C. / Mainolfi, N. / 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. / Wu, M.S. / Capparelli, M. / Ramqaj, R. / Solovay, C. / Cumin, F. / Smith, T.M. / Ferrara, L. / Lee, W. / Long, D. / Prentiss, M. / Erkenez, A.D. / 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. / Wiesmann, C. / 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 / pdbx_struct_conn_angle / struct_conn
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 / _pdbx_struct_conn_angle.ptnr1_PDB_ins_code / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_symmetry / _pdbx_struct_conn_angle.ptnr3_PDB_ins_code / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_ptnr1_PDB_ins_code / _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.ptnr1_symmetry / _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_symmetry
Revision 1.3Nov 6, 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,16011
Polymers65,9122
Non-polymers1,2489
Water6,179343
1
AAA: Complement factor B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,4664
Polymers32,9561
Non-polymers5113
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
BBB: Complement factor B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,6937
Polymers32,9561
Non-polymers7376
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)54.696, 97.656, 61.881
Angle α, β, γ (deg.)90.000, 100.309, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain: (Details: Chains A B)

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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.: 2
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-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-MVW / 5,7-dimethyl-4-[[(2~{S})-2-phenylpiperidin-1-yl]methyl]-1~{H}-indole


Mass: 318.455 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H26N2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 343 / 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: 2.47 Å3/Da / Density % sol: 50.14 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop
Details: 25% PEG3350, 0.1M BIS-TRIS PH 6.5, 0.2M AMMONIUM SULFATE, 0.1 MM ZNCL2, 1 mM inhibitor

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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: Jun 1, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.7→60.87 Å / Num. obs: 69872 / % possible obs: 99.3 % / Observed criterion σ(I): -3 / Redundancy: 3.4 % / Rmerge(I) obs: 0.051 / Rrim(I) all: 0.061 / Net I/σ(I): 13.55
Reflection shellResolution: 1.7→1.75 Å / Rmerge(I) obs: 0.259 / Mean I/σ(I) obs: 3.86 / Num. unique obs: 5823 / Rrim(I) all: 0.356

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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: 1.7→53.813 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.937 / SU B: 2.696 / SU ML: 0.085 / Cross valid method: FREE R-VALUE / ESU R: 0.111 / ESU R Free: 0.112
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2383 3486 5.001 %
Rwork0.1975 --
all0.199 --
obs-69712 99.289 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 28.47 Å2
Baniso -1Baniso -2Baniso -3
1-0.015 Å20 Å2-0.133 Å2
2--0.022 Å2-0 Å2
3---0.01 Å2
Refinement stepCycle: LAST / Resolution: 1.7→53.813 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4447 0 75 343 4865
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0124682
X-RAY DIFFRACTIONr_angle_refined_deg1.671.6576367
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5135577
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.44522.543232
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.38315796
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.0251527
X-RAY DIFFRACTIONr_chiral_restr0.1230.2595
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.023558
X-RAY DIFFRACTIONr_nbd_refined0.2140.22072
X-RAY DIFFRACTIONr_nbtor_refined0.3160.23168
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.120.2320
X-RAY DIFFRACTIONr_metal_ion_refined0.0610.22
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2120.258
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1380.217
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined0.1080.22
X-RAY DIFFRACTIONr_mcbond_it2.5982.5832281
X-RAY DIFFRACTIONr_mcangle_it3.7063.8522846
X-RAY DIFFRACTIONr_scbond_it3.8123.0222401
X-RAY DIFFRACTIONr_scangle_it5.5674.3573514
X-RAY DIFFRACTIONr_lrange_it7.10436.0877096
X-RAY DIFFRACTIONr_ncsr_local_group_10.10.058648
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
1.7-1.7440.3512570.30448800.30751470.6760.7199.80570.235
1.744-1.7920.3122520.28147840.28350410.7720.79299.90080.217
1.792-1.8440.262440.25646480.25648990.8640.86499.85710.201
1.844-1.90.2852380.24145260.24447810.8610.87999.64440.19
1.9-1.9630.2792300.24743630.24946230.8740.89299.35110.198
1.963-2.0310.2412220.20142140.20344850.9140.92798.90750.172
2.031-2.1080.2622140.19940600.20342970.9020.92199.46470.178
2.108-2.1940.2332070.19539370.19741550.9250.93999.73530.18
2.194-2.2910.2611970.21937500.22139940.9140.92998.82320.196
2.291-2.4030.2281890.18635830.18837850.9320.94299.65650.181
2.403-2.5330.2321790.18234160.18536170.9320.94699.39180.179
2.533-2.6860.2591720.19632500.19934500.9150.93799.18840.198
2.686-2.8710.2641600.19930420.20232480.9090.93198.58370.206
2.871-3.10.2531470.19728040.229950.9120.93598.53090.213
3.1-3.3950.2051380.1926130.19127750.9390.94599.13510.21
3.395-3.7940.2331220.19523320.19724900.9380.94398.55420.217
3.794-4.3770.191100.15920800.16122230.9550.96498.51550.192
4.377-5.3520.201930.14417680.14718940.9590.97398.25770.181
5.352-7.5320.206730.19113880.19214720.9490.95699.25270.234
7.532-53.8130.249420.217880.2118390.9430.95898.92730.265

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