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- PDB-3oad: Design and optimization of new piperidines as renin inhibitors -

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Basic information

Entry
Database: PDB / ID: 3oad
TitleDesign and optimization of new piperidines as renin inhibitors
Components(Renin) x 2
KeywordsHYDROLASE / Protease / Blood
Function / homology
Function and homology information


renin / mesonephros development / juxtaglomerular apparatus development / response to cGMP / renin-angiotensin regulation of aldosterone production / drinking behavior / regulation of MAPK cascade / response to immobilization stress / amyloid-beta metabolic process / Metabolism of Angiotensinogen to Angiotensins ...renin / mesonephros development / juxtaglomerular apparatus development / response to cGMP / renin-angiotensin regulation of aldosterone production / drinking behavior / regulation of MAPK cascade / response to immobilization stress / amyloid-beta metabolic process / Metabolism of Angiotensinogen to Angiotensins / cell maturation / angiotensin maturation / response to cAMP / insulin-like growth factor receptor binding / hormone-mediated signaling pathway / kidney development / regulation of blood pressure / male gonad development / apical part of cell / cellular response to xenobiotic stimulus / 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: 2.17 Å
AuthorsPrade, L.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Design and optimization of new piperidines as renin inhibitors.
Authors: Corminboeuf, O. / Bezencon, O. / Grisostomi, C. / Remen, L. / Richard-Bildstein, S. / Bur, D. / Prade, L. / Hess, P. / Strickner, P. / Fischli, W. / Steiner, B. / Treiber, A.
History
DepositionAug 5, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 3, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Jul 29, 2020Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_conn / struct_ref_seq_dif / 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_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_label_asym_id / _struct_ref_seq_dif.details
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.3Nov 6, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Renin
B: Renin
C: Renin
D: Renin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,0798
Polymers75,3114
Non-polymers1,7684
Water2,612145
1
A: Renin
B: Renin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,5404
Polymers37,6562
Non-polymers8842
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4050 Å2
ΔGint-17 kcal/mol
Surface area14710 Å2
MethodPISA
2
C: Renin
D: Renin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,5404
Polymers37,6562
Non-polymers8842
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3950 Å2
ΔGint-19 kcal/mol
Surface area15110 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.666, 93.405, 118.271
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: 18225.455 Da / Num. of mol.: 2 / Fragment: UNP RESIDUE 67-232
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: Protein Renin


Mass: 19430.055 Da / Num. of mol.: 2 / Fragment: UNP RESIDUE 237-406
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
#3: 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
#4: Chemical ChemComp-LPO / (3S,4R)-N-[2-chloro-5-(2-methoxyethyl)benzyl]-N-cyclopropyl-4-{6-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]pyridin-3-yl}-4-hydroxypiperidine-3-carboxamide / (3'S,4'R)-6-[2-(2,6-Dichloro-4-methyl-phenoxy)-ethoxy]-4'-hydroxy-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid [2-chloro-5-(2-methoxy-ethyl)-benzyl]-cyclopropyl-amide


Mass: 663.031 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C33H38Cl3N3O5
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 145 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY
Sequence detailsAUTHORS STATE THAT A SEQUENCE COMPOSED OF FOUR RESIDUES (-233ENS236Q-) HAS BEEN CLEAVED AWAY TO ...AUTHORS STATE THAT A SEQUENCE COMPOSED OF FOUR RESIDUES (-233ENS236Q-) HAS BEEN CLEAVED AWAY TO ACTIVATE THE PROTEASE

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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: 2.45 Å3/Da / Density % sol: 49.8 %
Crystal growMethod: vapor diffusion, sitting drop / pH: 4.75
Details: 20-30% PEG 4000 0.6M KCl or NaCl, pH 4.75, VAPOR DIFFUSION, SITTING DROP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Aug 20, 2006
RadiationMonochromator: si 111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.17→59.1 Å / Num. all: 39861 / Num. obs: 35174 / % possible obs: 87.5 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Rmerge(I) obs: 0.08 / Net I/σ(I): 7.8
Reflection shellResolution: 2.17→2.3 Å / % possible all: 37.3

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Processing

Software
NameVersionClassification
MAR345dtbdata collection
MOLREPphasing
REFMAC5.2.0019refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.17→59.1 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.9 / SU B: 5.451 / SU ML: 0.139 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.27 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.29064 1772 5 %RANDOM
Rwork0.2133 ---
obs0.21713 33347 88.1 %-
all-35174 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 46.256 Å2
Baniso -1Baniso -2Baniso -3
1--1.39 Å20 Å20 Å2
2--5.45 Å20 Å2
3----4.06 Å2
Refinement stepCycle: LAST / Resolution: 2.17→59.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5161 0 116 145 5422
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0225427
X-RAY DIFFRACTIONr_angle_refined_deg1.5061.9787374
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.615667
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.38923.982221
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.99915856
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.3651520
X-RAY DIFFRACTIONr_chiral_restr0.1040.2819
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.024074
X-RAY DIFFRACTIONr_nbd_refined0.2210.22425
X-RAY DIFFRACTIONr_nbtor_refined0.3130.23659
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.150.2300
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2390.241
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1370.211
X-RAY DIFFRACTIONr_mcbond_it1.85433378
X-RAY DIFFRACTIONr_mcangle_it2.88155346
X-RAY DIFFRACTIONr_scbond_it1.88732355
X-RAY DIFFRACTIONr_scangle_it2.74152022
LS refinement shellResolution: 2.17→2.225 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.275 28 -
Rwork0.298 462 -
obs--16.83 %

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