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- PDB-6t8v: Complement factor B in complex with (S)-5,7-Dimethyl-4-((2-phenyl... -

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Basic information

Entry
Database: PDB / ID: 6t8v
TitleComplement factor B in complex with (S)-5,7-Dimethyl-4-((2-phenylpiperidin-1-yl)methyl)-1H-indole
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 / von Willebrand factor (vWF) type A domain / VWFA domain profile. ...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 / von Willebrand factor (vWF) type A domain / VWFA domain profile. / 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-MVK / Complement factor B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.29 Å
AuthorsMainolfi, N. / Ehara, T. / Karki, R.G. / Anderson, K. / Mac Sweeney, A. / Wiesmann, C. / Adams, C. / Mainolfi, N. / Liao, S.-M. / Argikar, U.A. ...Mainolfi, N. / Ehara, T. / Karki, R.G. / Anderson, K. / Mac Sweeney, A. / 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. / 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. / 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.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.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.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 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,24811
Polymers65,9122
Non-polymers1,3369
Water1,964109
1
AAA: Complement factor B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,5104
Polymers32,9561
Non-polymers5553
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
BBB: Complement factor B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,7377
Polymers32,9561
Non-polymers7816
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)54.652, 97.487, 61.975
Angle α, β, γ (deg.)90.000, 100.465, 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-MVK / 4-[(2~{S})-1-[(5,7-dimethyl-1~{H}-indol-4-yl)methyl]piperidin-2-yl]benzoic acid


Mass: 362.465 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H26N2O2 / 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.: 109 / 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: 2.46 Å3/Da / Density % sol: 50.06 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / Details: 25% PEG3350, 0.1M HEPES PH 7.5, 5 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: Sep 18, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.29→60.92 Å / Num. obs: 28558 / % possible obs: 99.1 % / Redundancy: 3.4 % / Rmerge(I) obs: 0.102 / Rrim(I) all: 0.121 / Net I/σ(I): 12.22
Reflection shellResolution: 2.29→2.36 Å / Rmerge(I) obs: 0.38 / Mean I/σ(I) obs: 4.16 / Num. unique obs: 2476 / Rrim(I) all: 0.45 / % possible all: 98.1

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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: 2.29→48.743 Å / Cor.coef. Fo:Fc: 0.927 / Cor.coef. Fo:Fc free: 0.891 / SU B: 7.086 / SU ML: 0.172 / Cross valid method: FREE R-VALUE / ESU R: 0.347 / ESU R Free: 0.245
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2539 1428 5.001 %
Rwork0.2023 --
all0.205 --
obs-28552 99.153 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 24.576 Å2
Baniso -1Baniso -2Baniso -3
1--0.018 Å20 Å2-0.072 Å2
2--0.076 Å2-0 Å2
3----0.03 Å2
Refinement stepCycle: LAST / Resolution: 2.29→48.743 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4402 0 81 109 4592
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0124636
X-RAY DIFFRACTIONr_angle_refined_deg1.4971.6636294
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.65571
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.66722.533229
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.52915789
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.5131527
X-RAY DIFFRACTIONr_chiral_restr0.1180.2590
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.023484
X-RAY DIFFRACTIONr_nbd_refined0.2030.21842
X-RAY DIFFRACTIONr_nbtor_refined0.3130.23073
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1380.2157
X-RAY DIFFRACTIONr_metal_ion_refined0.0130.22
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2240.243
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1550.28
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined0.0470.23
X-RAY DIFFRACTIONr_mcbond_it1.9932.3182260
X-RAY DIFFRACTIONr_mcangle_it3.2913.462821
X-RAY DIFFRACTIONr_scbond_it2.862.6052376
X-RAY DIFFRACTIONr_scangle_it4.4323.7693467
X-RAY DIFFRACTIONr_lrange_it6.730.2236621
X-RAY DIFFRACTIONr_ncsr_local_group_10.1080.058353
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
2.29-2.3490.3371030.2619510.26421010.8580.88497.7630.228
2.349-2.4140.3181020.2519470.25320720.830.88498.890.223
2.414-2.4840.3181000.24718970.2520240.8370.87598.6660.219
2.484-2.560.308960.23718210.2419390.8570.89198.86540.213
2.56-2.6430.3930.22917680.23218660.8560.89699.7320.204
2.643-2.7360.331920.22417490.22918480.8690.90499.62120.206
2.736-2.8390.272870.2116500.21317400.8880.91799.82760.195
2.839-2.9540.285860.21316330.21617200.8880.91699.94190.201
2.954-3.0850.25810.21115550.21316380.8930.91699.87790.2
3.085-3.2350.273790.20414850.20815670.8960.92599.80850.2
3.235-3.4090.233740.20714180.20814950.930.93799.79930.205
3.409-3.6150.253700.2113250.21213980.9280.93799.78540.21
3.615-3.8630.273640.20312160.20713300.9140.94696.24060.198
3.863-4.170.208610.16411520.16612220.950.96199.26350.169
4.17-4.5650.164570.14610840.14711440.9740.97399.73780.155
4.565-5.0980.162510.1519740.15110320.9630.96999.32170.164
5.098-5.8760.233440.1638460.1669000.9360.95598.88890.173
5.876-7.1710.23400.1757410.1777830.9390.95899.74460.188
7.171-10.0340.201300.1825760.1836100.9580.95799.34430.206
10.034-48.7430.296180.2613360.2633640.9370.92397.25270.285

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