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- PDB-4gj6: Crystal structure of renin in complex with NVP-AYZ832 (compound 6a) -

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Basic information

Entry
Database: PDB / ID: 4gj6
TitleCrystal structure of renin in complex with NVP-AYZ832 (compound 6a)
ComponentsRenin
KeywordsHYDROLASE/HYDROLASE INHIBITOR / renin inhibitor / pharmacophore search / trans-3 / 4-disubstituted pyrrolidine / 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 / MOLECULAR REPLACEMENT / Resolution: 2.58 Å
AuthorsOstermann, N. / Zink, F. / Kroemer, M.
CitationJournal: J.Med.Chem. / Year: 2013
Title: The Discovery of Novel Potent trans-3,4-Disubstituted Pyrrolidine Inhibitors of the Human Aspartic Protease Renin from in Silico Three-Dimensional (3D) Pharmacophore Searches.
Authors: Lorthiois, E. / Breitenstein, W. / Cumin, F. / Ehrhardt, C. / Francotte, E. / Jacoby, E. / Ostermann, N. / Sellner, H. / Kosaka, T. / Webb, R.L. / Rigel, D.F. / Hassiepen, U. / Richert, P. / ...Authors: Lorthiois, E. / Breitenstein, W. / Cumin, F. / Ehrhardt, C. / Francotte, E. / Jacoby, E. / Ostermann, N. / Sellner, H. / Kosaka, T. / Webb, R.L. / Rigel, D.F. / Hassiepen, U. / Richert, P. / Wagner, T. / Maibaum, J.
History
DepositionAug 9, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 6, 2013Provider: repository / Type: Initial release
Revision 1.1Apr 10, 2013Group: Database references
Revision 1.2Jul 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_leaving_atom_flag / _struct_conn.pdbx_role
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.3Sep 13, 2023Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Renin
B: Renin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,77211
Polymers74,5342
Non-polymers2,2389
Water3,387188
1
A: Renin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,3385
Polymers37,2671
Non-polymers1,0714
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Renin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,4346
Polymers37,2671
Non-polymers1,1675
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)67.006, 110.930, 130.366
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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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 / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P00797, renin
#2: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


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-0LS / N-{[(3S,4S)-4-benzylpyrrolidin-3-yl]methyl}-4-chloro-N-phenylaniline


Mass: 376.922 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C24H25ClN2
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 188 / 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: 3.25 Å3/Da / Density % sol: 62.16 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: reservoir: 18-21% PEG4000, 0.4-0.6 M sodium chloride, 50 mM sodium citrate, pH 4-5, protein solution: 10-15 mg/mL protein, 25 mM sodium chloride, 12.5 mM Tris, pH 8, drop: 1 uL protein ...Details: reservoir: 18-21% PEG4000, 0.4-0.6 M sodium chloride, 50 mM sodium citrate, pH 4-5, protein solution: 10-15 mg/mL protein, 25 mM sodium chloride, 12.5 mM Tris, pH 8, drop: 1 uL protein solution + 1 uL reservoir, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 95 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.97948 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Dec 18, 2003
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97948 Å / Relative weight: 1
ReflectionResolution: 2.58→52.5 Å / Num. obs: 23603 / % possible obs: 75.8 % / Observed criterion σ(F): 0 / Biso Wilson estimate: 50.65 Å2 / Rmerge(I) obs: 0.072 / Net I/σ(I): 15
Reflection shellResolution: 2.58→2.69 Å / Rmerge(I) obs: 0.38 / Mean I/σ(I) obs: 2.8 / % possible all: 68.1

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Processing

Software
NameVersionClassification
MOLREPphasing
BUSTER2.11.2refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2V0Z

2v0z


Resolution: 2.58→52.49 Å / Cor.coef. Fo:Fc: 0.9429 / Cor.coef. Fo:Fc free: 0.9071 / SU R Cruickshank DPI: 0.851 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 1.071 / SU Rfree Blow DPI: 0.3 / SU Rfree Cruickshank DPI: 0.301 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2211 2377 10.08 %RANDOM
Rwork0.1705 ---
obs0.1756 23575 75.33 %-
Displacement parametersBiso mean: 34.09 Å2
Baniso -1Baniso -2Baniso -3
1--1.1668 Å20 Å20 Å2
2--0.3352 Å20 Å2
3---0.8316 Å2
Refine analyzeLuzzati coordinate error obs: 0.278 Å
Refinement stepCycle: LAST / Resolution: 2.58→52.49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5117 0 151 188 5456
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.015399HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.237327HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1783SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes111HARMONIC2
X-RAY DIFFRACTIONt_gen_planes788HARMONIC5
X-RAY DIFFRACTIONt_it5399HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.58
X-RAY DIFFRACTIONt_other_torsion18.54
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion717SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact6090SEMIHARMONIC4
LS refinement shellResolution: 2.58→2.69 Å / Total num. of bins used: 12
RfactorNum. reflection% reflection
Rfree0.2979 249 10.32 %
Rwork0.2119 2163 -
all0.2209 2412 -
obs-2412 75.33 %

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