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- PDB-5nar: Complement factor D in complex with the inhibitor (S)-pyrrolidine... -

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Basic information

Entry
Database: PDB / ID: 5nar
TitleComplement factor D in complex with the inhibitor (S)-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl)-amide] 2-[(3-trifluoromethoxy-phenyl)-amide]
ComponentsComplement factor DFactor D
KeywordsHYDROLASE
Function / homology
Function and homology information


complement factor D / Alternative complement activation / complement activation, alternative pathway / complement activation / serine-type peptidase activity / platelet alpha granule lumen / response to bacterium / Platelet degranulation / secretory granule lumen / ficolin-1-rich granule lumen ...complement factor D / Alternative complement activation / complement activation, alternative pathway / complement activation / serine-type peptidase activity / platelet alpha granule lumen / response to bacterium / Platelet degranulation / secretory granule lumen / ficolin-1-rich granule lumen / serine-type endopeptidase activity / Neutrophil degranulation / proteolysis / extracellular exosome / extracellular region
Similarity search - Function
Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, histidine active site. / Serine proteases, trypsin domain profile. / Trypsin-like serine protease / Serine proteases, trypsin family, serine active site. / Serine proteases, trypsin domain / Trypsin / Trypsin-like serine proteases ...Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, histidine active site. / Serine proteases, trypsin domain profile. / Trypsin-like serine protease / Serine proteases, trypsin family, serine active site. / Serine proteases, trypsin domain / Trypsin / Trypsin-like serine proteases / Thrombin, subunit H / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
Chem-8RW / Complement factor D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.55 Å
AuthorsMac Sweeney, A. / Ostermann, N.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Discovery of Highly Potent and Selective Small-Molecule Reversible Factor D Inhibitors Demonstrating Alternative Complement Pathway Inhibition in Vivo.
Authors: Lorthiois, E. / Anderson, K. / Vulpetti, A. / Rogel, O. / Cumin, F. / Ostermann, N. / Steinbacher, S. / Mac Sweeney, A. / Delgado, O. / Liao, S.M. / Randl, S. / Rudisser, S. / Dussauge, S. / ...Authors: Lorthiois, E. / Anderson, K. / Vulpetti, A. / Rogel, O. / Cumin, F. / Ostermann, N. / Steinbacher, S. / Mac Sweeney, A. / Delgado, O. / Liao, S.M. / Randl, S. / Rudisser, S. / Dussauge, S. / Fettis, K. / Kieffer, L. / de Erkenez, A. / Yang, L. / Hartwieg, C. / Argikar, U.A. / La Bonte, L.R. / Newton, R. / Kansara, V. / Flohr, S. / Hommel, U. / Jaffee, B. / Maibaum, J.
History
DepositionFeb 28, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 28, 2017Provider: repository / Type: Initial release
Revision 1.1Jul 26, 2017Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_id_ASTM ..._citation.country / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Complement factor D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,3113
Polymers24,7391
Non-polymers5712
Water3,369187
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area170 Å2
ΔGint-13 kcal/mol
Surface area9750 Å2
MethodPISA
Unit cell
Length a, b, c (Å)77.802, 44.516, 63.744
Angle α, β, γ (deg.)90.00, 117.69, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Complement factor D / Factor D / Adipsin / C3 convertase activator / Properdin factor D


Mass: 24739.121 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P00746, complement factor D
#2: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-8RW / (2~{S})-~{N}1-(1-aminocarbonylindol-3-yl)-~{N}2-[3-(trifluoromethyloxy)phenyl]pyrrolidine-1,2-dicarboxamide


Mass: 475.421 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H20F3N5O4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 187 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsP2SEQ ANNOTATION (DBREF, SEQADV, MODRES, REMARK 465, COMPND, SOURCE RECORDS) WAS ADDED SEMI- ...P2SEQ ANNOTATION (DBREF, SEQADV, MODRES, REMARK 465, COMPND, SOURCE RECORDS) WAS ADDED SEMI-AUTOMATICALLY TO THIS ENTRY. CONSTRUCT BOUNDARIES IN DBREF MAY BE INACCURATE IF THE ORIGINAL DEPOSITION DID NOT SPECIFY A PROTRACK CRYSTALLIZATION SEQUENCE.

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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: 1.98 Å3/Da / Density % sol: 37.74 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop
Details: MM NACL, 0.5MM NVP-BVT244-NX-1 + 1 UL RESERVOIR SOLUTION

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1.0001 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Jan 24, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength
IDWavelength (Å)Relative weight
11.00011
21.00011
ReflectionResolution: 1.37→56.44 Å / Num. obs: 40131 / % possible obs: 98.3 % / Observed criterion σ(I): -3 / Redundancy: 3.49 % / Rmerge(I) obs: 0.085 / Net I/σ(I): 9.9
Reflection shellResolution: 1.37→1.42 Å / Redundancy: 2.56 % / Rmerge(I) obs: 0.392 / Mean I/σ(I) obs: 2.93 / % possible all: 90

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1HFLF

Resolution: 1.55→35.58 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.91 / SU B: 3.856 / SU ML: 0.064 / Cross valid method: THROUGHOUT / ESU R: 0.108 / ESU R Free: 0.097 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23101 1402 5 %RANDOM
Rwork0.15515 ---
obs0.15891 26638 99.4 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 13.961 Å2
Baniso -1Baniso -2Baniso -3
1-0.03 Å2-0 Å20.04 Å2
2---0.16 Å2-0 Å2
3---0.05 Å2
Refinement stepCycle: 1 / Resolution: 1.55→35.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1621 0 39 187 1847
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.030.0191737
X-RAY DIFFRACTIONr_bond_other_d0.0020.021615
X-RAY DIFFRACTIONr_angle_refined_deg2.4571.9692377
X-RAY DIFFRACTIONr_angle_other_deg1.2652.9853740
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.0465226
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.06822.75469
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.97815272
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.3741516
X-RAY DIFFRACTIONr_chiral_restr0.3330.2267
X-RAY DIFFRACTIONr_gen_planes_refined0.0160.0211958
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02340
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_it2.821.093885
X-RAY DIFFRACTIONr_mcbond_other2.5871.088884
X-RAY DIFFRACTIONr_mcangle_it3.0971.6291107
X-RAY DIFFRACTIONr_mcangle_other3.1591.6331108
X-RAY DIFFRACTIONr_scbond_it4.0761.478850
X-RAY DIFFRACTIONr_scbond_other4.0731.477851
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.4552.0681267
X-RAY DIFFRACTIONr_long_range_B_refined4.54114.8031905
X-RAY DIFFRACTIONr_long_range_B_other4.5414.7991906
X-RAY DIFFRACTIONr_rigid_bond_restr3.90133349
X-RAY DIFFRACTIONr_sphericity_free24.3215111
X-RAY DIFFRACTIONr_sphericity_bonded9.46753385
LS refinement shellResolution: 1.55→1.59 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.286 103 -
Rwork0.143 1971 -
obs--99.81 %

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