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- PDB-8dea: Scaffold Hopping via Ring Opening Enables Identification of Acycl... -

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Basic information

Entry
Database: PDB / ID: 8dea
TitleScaffold Hopping via Ring Opening Enables Identification of Acyclic Compounds as New Complement Factor D Inhibitors
ComponentsComplement factor D
KeywordsHYDROLASE/HYDROLASE INHIBITOR / serine protease inhibitor complex / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


complement factor D / Alternative complement activation / complement activation / complement activation, alternative pathway / serine-type peptidase activity / platelet alpha granule lumen / protein maturation / response to bacterium / Platelet degranulation / secretory granule lumen ...complement factor D / Alternative complement activation / complement activation / complement activation, alternative pathway / serine-type peptidase activity / platelet alpha granule lumen / protein maturation / response to bacterium / Platelet degranulation / secretory granule lumen / ficolin-1-rich granule lumen / serine-type endopeptidase activity / Neutrophil degranulation / proteolysis / extracellular space / extracellular exosome / extracellular region
Similarity search - Function
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
Similarity search - Domain/homology
Chem-R7X / Complement factor D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.214 Å
AuthorsRaman, K. / Babu, Y.S.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Bioorg.Med.Chem. / Year: 2022
Title: Scaffold hopping via ring opening enables identification of acyclic compounds as new complement Factor D inhibitors.
Authors: Zhang, W. / Wu, M. / Vadlakonda, S. / Juarez, L. / Cheng, X. / Muppa, S. / Chintareddy, V. / Vogeti, L. / Kellogg-Yelder, D. / Williams, J. / Polach, K. / Chen, X. / Raman, K. / Babu, Y.S. / Kotian, P.
History
DepositionJun 20, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 2, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
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: Complement factor D
B: Complement factor D
C: Complement factor D
D: Complement factor D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,29310
Polymers98,3884
Non-polymers1,9056
Water1,51384
1
A: Complement factor D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,0272
Polymers24,5971
Non-polymers4301
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Complement factor D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,0272
Polymers24,5971
Non-polymers4301
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Complement factor D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,2114
Polymers24,5971
Non-polymers6143
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Complement factor D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,0272
Polymers24,5971
Non-polymers4301
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)44.898, 73.032, 240.864
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP22121

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Components

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


Mass: 24596.965 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CFD, DF, PFD / Cell (production host): Embryonic kidney / Cell line (production host): Hek293 / Production host: Homo sapiens (human) / References: UniProt: P00746, complement factor D
#2: Chemical
ChemComp-R7X / 1-[(3-acetylphenyl)acetyl]-N-(6-bromopyridin-2-yl)-L-prolinamide


Mass: 430.295 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C20H20BrN3O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 84 / 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: 2.13 Å3/Da / Density % sol: 42.25 % / Description: square blocks
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.8 / Details: peg4k 25% , 0.1M MES 5.8 buffer / PH range: 6.4

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Data collection

DiffractionMean temperature: 170 K / Ambient temp details: cryostream / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.5418 Å
DetectorType: DECTRIS PILATUS 200K / Detector: PIXEL / Date: May 12, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.2→50 Å / Num. obs: 36438 / % possible obs: 74.5 % / Redundancy: 3.2 % / CC1/2: 0.771 / CC star: 0.993 / Rmerge(I) obs: 0.15 / Rpim(I) all: 0.311 / Χ2: 0.861 / Net I/σ(I): 5.4
Reflection shellResolution: 2.2→2.28 Å / Redundancy: 1.6 % / Num. unique obs: 1919 / CC1/2: 0.771 / CC star: 0.923 / Χ2: 0.532 / % possible all: 46.1

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Processing

Software
NameVersionClassification
REFMAC5.8.0350refinement
HKL-3000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1dic

1dic


Resolution: 2.214→46.46 Å / Cor.coef. Fo:Fc: 0.93 / Cor.coef. Fo:Fc free: 0.879 / WRfactor Rfree: 0.281 / WRfactor Rwork: 0.213 / SU B: 9.716 / SU ML: 0.238 / Average fsc free: 0.9334 / Average fsc work: 0.9623 / Cross valid method: FREE R-VALUE / ESU R: 0.557 / ESU R Free: 0.321
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2998 1694 4.897 %
Rwork0.225 32897 -
all0.229 --
obs-34591 85.164 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 33.495 Å2
Baniso -1Baniso -2Baniso -3
1--0.048 Å2-0 Å2-0 Å2
2--0.06 Å20 Å2
3----0.011 Å2
Refinement stepCycle: LAST / Resolution: 2.214→46.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6484 0 120 84 6688
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0126750
X-RAY DIFFRACTIONr_bond_other_d0.0030.0166216
X-RAY DIFFRACTIONr_angle_refined_deg1.3721.6549186
X-RAY DIFFRACTIONr_angle_other_deg0.5331.57614472
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.6375856
X-RAY DIFFRACTIONr_dihedral_angle_2_deg19.6851064
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.172101052
X-RAY DIFFRACTIONr_dihedral_angle_6_deg14.43510268
X-RAY DIFFRACTIONr_chiral_restr0.0560.21034
X-RAY DIFFRACTIONr_chiral_restr_other1.0070.220
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.027772
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021248
X-RAY DIFFRACTIONr_nbd_refined0.2170.21159
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1990.25881
X-RAY DIFFRACTIONr_nbtor_refined0.1630.23125
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0820.23789
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1530.2161
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2290.250
X-RAY DIFFRACTIONr_nbd_other0.2290.2124
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.3430.27
X-RAY DIFFRACTIONr_mcbond_it2.7623.3453456
X-RAY DIFFRACTIONr_mcbond_other2.7623.3453456
X-RAY DIFFRACTIONr_mcangle_it4.264.994296
X-RAY DIFFRACTIONr_mcangle_other4.2614.9934297
X-RAY DIFFRACTIONr_scbond_it2.7563.6043294
X-RAY DIFFRACTIONr_scbond_other2.7563.6043295
X-RAY DIFFRACTIONr_scangle_it4.2195.2854890
X-RAY DIFFRACTIONr_scangle_other4.2195.2854891
X-RAY DIFFRACTIONr_lrange_it7.31146.3666864
X-RAY DIFFRACTIONr_lrange_other7.30746.2676861
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
2.214-2.2710.353640.2714100.27429370.9140.94750.18730.257
2.271-2.3330.3231020.2718850.27328400.9280.94969.96480.256
2.333-2.4010.348920.26421410.26728120.9180.95279.40970.248
2.401-2.4740.3461190.26721720.27127250.9120.95284.07340.25
2.474-2.5550.3331020.25822240.26126210.920.95588.74480.24
2.555-2.6450.3341080.24522600.24925870.920.96191.53460.221
2.645-2.7440.3751240.24421150.2524360.9260.96191.9130.219
2.744-2.8560.3581190.25520760.2624010.9190.95791.42020.229
2.856-2.9820.292990.23519890.23822970.9350.96490.90120.211
2.982-3.1270.3351000.22619290.23121810.9290.96693.03070.206
3.127-3.2950.335960.2518730.25421010.9230.95993.71730.231
3.295-3.4940.281910.22117380.22419910.9550.97291.86340.207
3.494-3.7340.27830.22916180.23118870.9530.97190.14310.221
3.734-4.0310.275830.20414480.20817380.950.97688.08980.196
4.031-4.4120.222570.17913380.1816150.9680.97986.37770.171
4.412-4.9280.231640.15512100.15914960.9780.98585.16040.151
4.928-5.6790.284500.20110940.20513350.9560.97885.69290.196
5.679-6.930.311610.2399910.24311200.9550.96793.92860.233
6.93-9.6930.294530.1898450.1959140.9530.97798.24950.187
9.693-46.460.33270.2955410.2965780.9120.93698.26990.302

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