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- PDB-3sfc: Structure-Based Optimization of Potent 4- and 6-Azaindole-3-Carbo... -

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Basic information

Entry
Database: PDB / ID: 3sfc
TitleStructure-Based Optimization of Potent 4- and 6-Azaindole-3-Carboxamides as Renin Inhibitors
ComponentsRenin
KeywordsHYDROLASE/HYDROLASE INHIBITOR / RENIN HUMAN / ASPARTYL PROTEASE / RENIN INHIBITION / HYPERTENSION / beta barrel / pepsin-like protease / glycosylation / extracellular space / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


renin / juxtaglomerular apparatus development / mesonephros development / response to cGMP / renin-angiotensin regulation of aldosterone production / drinking behavior / regulation of MAPK cascade / response to immobilization stress / amyloid-beta metabolic process / angiotensin maturation ...renin / juxtaglomerular apparatus development / mesonephros development / response to cGMP / renin-angiotensin regulation of aldosterone production / drinking behavior / regulation of MAPK cascade / response to immobilization stress / amyloid-beta metabolic process / angiotensin maturation / Metabolism of Angiotensinogen to Angiotensins / cell maturation / response to cAMP / insulin-like growth factor receptor binding / hormone-mediated signaling pathway / kidney development / regulation of blood pressure / male gonad development / cellular response to xenobiotic stimulus / apical part of cell / peptidase activity / response to lipopolysaccharide / aspartic-type endopeptidase activity / signaling receptor binding / proteolysis / extracellular space / extracellular region / plasma membrane
Similarity search - Function
Renin-like domain / Aspartic peptidase, N-terminal / A1 Propeptide / Eukaryotic aspartyl protease / Aspartic peptidase A1 family / Peptidase family A1 domain / Peptidase family A1 domain profile. / Cathepsin D, subunit A; domain 1 / Acid Proteases / Aspartic peptidase, active site ...Renin-like domain / Aspartic peptidase, N-terminal / A1 Propeptide / Eukaryotic aspartyl protease / Aspartic peptidase A1 family / Peptidase family A1 domain / Peptidase family A1 domain profile. / Cathepsin D, subunit A; domain 1 / Acid Proteases / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain superfamily / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.1 Å
AuthorsScheiper, B. / Matter, H. / Steinhagen, H. / Bocskei, Z. / Fleury, V. / McCort, G.
Citation
Journal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Structure-based optimization of potent 4- and 6-azaindole-3-carboxamides as renin inhibitors.
Authors: Scheiper, B. / Matter, H. / Steinhagen, H. / Bocskei, Z. / Fleury, V. / McCort, G.
#1: Journal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Discovery and optimization of a new class of potent and non-chiral indole-3-carboxamide-based renin inhibitors.
Authors: Scheiper, B. / Matter, H. / Steinhagen, H. / Stilz, U. / Bocskei, Z. / Fleury, V. / McCort, G.
History
DepositionJun 13, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 31, 2011Provider: repository / Type: Initial release
Revision 1.1May 23, 2012Group: Database references
Revision 1.2Nov 12, 2014Group: Structure summary
Revision 1.3Jul 29, 2020Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_conn / struct_site / struct_site_gen
Item: _chem_comp.name / _chem_comp.type ..._chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_label_asym_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Renin
B: Renin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,90711
Polymers74,5342
Non-polymers2,3739
Water8,701483
1
A: Renin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,8067
Polymers37,2671
Non-polymers1,5396
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Renin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1014
Polymers37,2671
Non-polymers8343
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
A: Renin
B: Renin
hetero molecules

A: Renin
B: Renin
hetero molecules

A: Renin
B: Renin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)230,72033
Polymers223,6026
Non-polymers7,11827
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation5_555z,x,y1
crystal symmetry operation9_555y,z,x1
Buried area20820 Å2
ΔGint-48 kcal/mol
Surface area75510 Å2
MethodPISA
4
A: Renin
B: Renin
hetero molecules

A: Renin
B: Renin
hetero molecules

A: Renin
B: Renin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)230,72033
Polymers223,6026
Non-polymers7,11827
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation5_555z,x,y1
crystal symmetry operation9_555y,z,x1
Buried area6890 Å2
ΔGint-18 kcal/mol
Surface area41750 Å2
MethodPISA
5
A: Renin
B: Renin
hetero molecules

A: Renin
B: Renin
hetero molecules

A: Renin
B: Renin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)230,72033
Polymers223,6026
Non-polymers7,11827
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation5_555z,x,y1
crystal symmetry operation9_555y,z,x1
Buried area5650 Å2
ΔGint-14 kcal/mol
Surface area42040 Å2
MethodPISA
Unit cell
Length a, b, c (Å)138.794, 138.794, 138.794
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number198
Space group name H-MP213

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Components

#1: Protein Renin / Angiotensinogenase


Mass: 37267.008 Da / Num. of mol.: 2 / Fragment: unp residues 67-406
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: REN / Cell line (production host): HEK / Production host: HOMO SAPIENS (human) / References: UniProt: P00797, renin
#2: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-S53 / [7-benzyl-2-(5-fluoro-2-methylphenoxy)-1-phenyl-1H-pyrrolo[2,3-c]pyridin-3-yl](piperazin-1-yl)methanone


Mass: 520.597 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C32H29FN4O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 483 / Source method: isolated from a natural source / Formula: H2O

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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: 2.99 Å3/Da / Density % sol: 58.85 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 4.5
Details: 0.05M CITRATE, 10-12% PEG3350, 0.6M NACL, 20 MG/ML RENIN, VAPOUR DIFFUSION, HANGING DROP, VAPOR DIFFUSION, HANGING DROP, temperature 298K, pH 4.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 1.07225 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Dec 6, 2007
RadiationMonochromator: mirror / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.07225 Å / Relative weight: 1
ReflectionResolution: 2.1→69.34 Å / Num. all: 51036 / Num. obs: 51036 / % possible obs: 98.2 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -5 / Redundancy: 2.5 % / Biso Wilson estimate: 33.835 Å2 / Rmerge(I) obs: 0.159 / Net I/σ(I): 3.3
Reflection shellResolution: 2.1→2.21 Å / Redundancy: 2.6 % / Rmerge(I) obs: 0.779 / Mean I/σ(I) obs: 1 / Rsym value: 0.779 / % possible all: 99.5

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
BUSTER-TNTrefinement
PDB_EXTRACT3.1data extraction
ADSCQuantumdata collection
MOSFLMdata reduction
AMoREphasing
BUSTER2.9.7refinement
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.1→62.07 Å / Cor.coef. Fo:Fc: 0.9126 / Cor.coef. Fo:Fc free: 0.9046 / Occupancy max: 1 / Occupancy min: 0.5 / SU R Cruickshank DPI: 0.207 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2428 2590 5.09 %RANDOM
Rwork0.2106 ---
all0.2122 50883 --
obs0.2122 50883 97.68 %-
Displacement parametersBiso max: 188.23 Å2 / Biso mean: 48.9062 Å2 / Biso min: 19.63 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refine analyzeLuzzati coordinate error obs: 0.301 Å
Refinement stepCycle: LAST / Resolution: 2.1→62.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5242 0 169 483 5894
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1838SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes118HARMONIC2
X-RAY DIFFRACTIONt_gen_planes811HARMONIC5
X-RAY DIFFRACTIONt_it5550HARMONIC20
X-RAY DIFFRACTIONt_chiral_improper_torsion724SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact6470SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d5550HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg7538HARMONIC21.27
X-RAY DIFFRACTIONt_omega_torsion3.34
X-RAY DIFFRACTIONt_other_torsion19.46
LS refinement shellResolution: 2.1→2.15 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2337 207 5.53 %
Rwork0.2191 3538 -
all0.2199 3745 -
obs--97.68 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.07690.2417-2.50332.37091.32170.86320.0117-0.0813-0.09570.11550.04140.01010.0607-0.0205-0.0531-0.0437-0.00080.0132-0.00610.0774-0.0619-18.1622-31.661313.0361
20.91592.1956-1.97532.24922.84960.0464-0.0170.0527-0.04640.004-0.00760.11740.0765-0.13270.0245-0.04570.0209-0.01160.00580.1020.0464-19.9147-34.68497.0862
31.14610.55340.56121.67830.31223.0702-0.02460.1283-0.2719-0.07670.2046-0.29860.11540.3757-0.18-0.16490.03320.0153-0.0693-0.0424-0.0296-8.0811-38.054-3.8728
41.09140.25670.48561.06730.26321.4788-0.0325-0.11730.00770.04610.0415-0.0456-0.10450.0925-0.009-0.04360.03-0.00790.0166-0.0009-0.0485-10.2488-16.381911.4453
51.8471-0.66470.57960.7892-0.28830.28670.006-0.0572-0.14160.15580.0837-0.08840.06330.0814-0.0897-0.03720.01660.0242-0.08830.03310.0152-27.7878-50.2084-1.925
62.39931.2548-0.14650-0.07181.4418-0.0390.12890.0046-0.0320.0629-0.0161-0.13230.1705-0.024-0.02320.03750.0927-0.0453-0.00840.04-31.3332-44.7568-4.9441
71.40770.3905-0.04872.0464-1.38092.5447-0.16330.2741-0.0598-0.26390.32480.28250.1419-0.3287-0.1615-0.1307-0.04430.0367-0.08680.0307-0.0285-43.8436-47.4718-14.5209
83.0157-0.2645-0.87563.1047-0.36682.6884-0.08530.4797-0.5442-0.20240.0503-0.53960.43050.27040.035-0.21140.07490.1224-0.1598-0.1520.1497-20.5051-61.0879-12.8233
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|-5 - A|11 }A-5 - 11
2X-RAY DIFFRACTION2{ A|146 - A|160 }A146 - 160
3X-RAY DIFFRACTION3{ A|161 - A|326 }A161 - 326
4X-RAY DIFFRACTION4{ A|12 - A|142 }A12 - 142
5X-RAY DIFFRACTION5{ B|-5 - B|11 }B-5 - 11
6X-RAY DIFFRACTION6{ B|146 - B|160 }B146 - 160
7X-RAY DIFFRACTION7{ B|161 - B|326 }B161 - 326
8X-RAY DIFFRACTION8{ B|12 - B|142 }B12 - 142

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