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- PDB-4xx4: Renin in complex with (4S)-4-isopropyl-4-methyl-6-oxo-1-(3-(2-oxo... -

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Basic information

Entry
Database: PDB / ID: 4xx4
TitleRenin in complex with (4S)-4-isopropyl-4-methyl-6-oxo-1-(3-(2-oxo-4-phenylpyrrolidin-1-yl)benzyl)tetrahydropyrimidin-2(1H)-iminium
ComponentsRenin
KeywordsHydrolase/Hydrolase Inhibitor / Animals / Antihypertensive Agents / Blood Pressure / Drug Design / Enzyme Inhibitors / Models / Molecular / Protein Conformation / Renin / Structure-Activity Relationship / 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 / angiotensin maturation / Metabolism of Angiotensinogen to Angiotensins ...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 / angiotensin maturation / Metabolism of Angiotensinogen to Angiotensins / amyloid-beta metabolic process / 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 / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsOrth, P.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2015
Title: Iminopyrimidinones: a novel pharmacophore for the development of orally active renin inhibitors.
Authors: McKittrick, B.A. / Caldwell, J.P. / Bara, T. / Boykow, G. / Chintala, M. / Clader, J. / Czarniecki, M. / Courneya, B. / Duffy, R. / Fleming, L. / Giessert, R. / Greenlee, W.J. / Heap, C. / ...Authors: McKittrick, B.A. / Caldwell, J.P. / Bara, T. / Boykow, G. / Chintala, M. / Clader, J. / Czarniecki, M. / Courneya, B. / Duffy, R. / Fleming, L. / Giessert, R. / Greenlee, W.J. / Heap, C. / Hong, L. / Huang, Y. / Iserloh, U. / Josien, H. / Khan, T. / Korfmacher, W. / Liang, X. / Mazzola, R. / Mitra, S. / Moore, K. / Orth, P. / Rajagopalan, M. / Roy, S. / Sakwa, S. / Strickland, C. / Vaccaro, H. / Voigt, J. / Wang, H. / Wong, J. / Zhang, R. / Zych, A.
History
DepositionJan 29, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 18, 2015Provider: repository / Type: Initial release
Revision 1.1Mar 16, 2016Group: Data collection
Revision 1.2Nov 22, 2017Group: Derived calculations / Refinement description / Category: pdbx_struct_oper_list / software / Item: _pdbx_struct_oper_list.symmetry_operation
Revision 1.3Apr 18, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_volume ..._citation.journal_abbrev / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.4Jul 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_role
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.5Sep 27, 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)75,5925
Polymers74,5342
Non-polymers1,0583
Water3,729207
1
A: Renin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,9073
Polymers37,2671
Non-polymers6402
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Renin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,6862
Polymers37,2671
Non-polymers4191
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)226,77715
Polymers223,6026
Non-polymers3,1759
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation5_555z,x,y1
crystal symmetry operation9_555y,z,x1
Buried area14110 Å2
ΔGint-57 kcal/mol
Surface area73070 Å2
MethodPISA
4
A: Renin
hetero molecules

A: Renin
hetero molecules

A: Renin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,7209
Polymers111,8013
Non-polymers1,9196
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation5_555z,x,y1
crystal symmetry operation9_555y,z,x1
Buried area3990 Å2
ΔGint-19 kcal/mol
Surface area40690 Å2
MethodPISA
5
B: Renin
hetero molecules

B: Renin
hetero molecules

B: Renin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,0576
Polymers111,8013
Non-polymers1,2563
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation5_555z,x,y1
crystal symmetry operation9_555y,z,x1
Buried area3950 Å2
ΔGint-31 kcal/mol
Surface area38550 Å2
MethodPISA
Unit cell
Length a, b, c (Å)142.410, 142.410, 142.410
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number198
Space group name H-MP213
Components on special symmetry positions
IDModelComponents
11A-618-

HOH

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Components

#1: Protein Renin / / Angiotensinogenase


Mass: 37267.008 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: LTLG NTTSSVILTN YMDTQYYGEI GIGTPPQTFK VVFDTGSSNV WVPSSKCSRL YTACVYHKLF DASDSSSYKH NGTELTLRYS TGTVSGFLSQ DIITVGGITV TQMFGEVTEM PALPFMLAEF DGVVGMGFIE QAIGRVTPIF DNIISQGVLK EDVFSFYYNR ...Details: LTLG NTTSSVILTN YMDTQYYGEI GIGTPPQTFK VVFDTGSSNV WVPSSKCSRL YTACVYHKLF DASDSSSYKH NGTELTLRYS TGTVSGFLSQ DIITVGGITV TQMFGEVTEM PALPFMLAEF DGVVGMGFIE QAIGRVTPIF DNIISQGVLK EDVFSFYYNR DSENSQSLGG QIVLGGSDPQ HYEGNFHYIN LIKTGVWQIQ MKGVSVGSST LLCEDGCLAL VDTGASYISG STSSIEKLME ALGAKKRLFD YVVKCNEGPT LPDISFHLGG KEYTLTSADY VFQESYSSKK LCTLAIHAMD IPPPTGPTWA LGATFIRKFY TEFDRRNNRI GFALAR
Source: (gene. exp.) Homo sapiens (human) / Gene: REN / Cell line (production host): 293 HEK / Production host: Homo sapiens (human) / 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 / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1
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-70Y / (2Z,6S)-2-imino-6-methyl-3-{3-[(4R)-2-oxo-4-phenylpyrrolidin-1-yl]benzyl}-6-(propan-2-yl)tetrahydropyrimidin-4(1H)-one


Mass: 418.531 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H30N4O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 207 / 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: 62.17 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / Details: 15% PEG3350, 625 mM NaCl and citrate buffer pH 4.6

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E DW / Wavelength: 1.54178 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: May 26, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 2.4→20 Å / Num. obs: 36079 / % possible obs: 95.5 % / Redundancy: 3 % / Rmerge(I) obs: 0.09 / Χ2: 1.065 / Net I/av σ(I): 7.891 / Net I/σ(I): 17.9 / Num. measured all: 108629
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible allMean I/σ(I) obs
2.4-2.492.40.42834851.127192.4
2.49-2.582.60.33533851.09791.3
2.58-2.72.70.25434301.06692
2.7-2.842.80.19635241.06494.2
2.84-3.0230.15336411.09897.3
3.02-3.253.20.12537501.07799.3
3.25-3.583.30.10237431.04499.5
3.58-4.093.30.08637501.01999.1
4.09-5.143.30.07437131.01797.210
5.14-203.40.05936581.07992.910

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Processing

Software
NameVersionClassification
BUSTER-TNTBUSTER 2.11.4refinement
DENZOdata reduction
SCALEPACKdata scaling
PDB_EXTRACT3.1data extraction
AMoREphasing
BUSTER2.11.4refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 2I4Q

2i4q


Resolution: 2.4→19.94 Å / Cor.coef. Fo:Fc: 0.9406 / Cor.coef. Fo:Fc free: 0.9366 / Occupancy max: 1 / Occupancy min: 0.5 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2293 1379 3.84 %RANDOM
Rwork0.2098 ---
obs0.2105 35898 95.11 %-
Displacement parametersBiso max: 122.73 Å2 / Biso mean: 46.9442 Å2 / Biso min: 23.13 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refine analyzeLuzzati coordinate error obs: 0.35 Å
Refinement stepCycle: LAST / Resolution: 2.4→19.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5120 0 76 207 5403
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1725SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes108HARMONIC2
X-RAY DIFFRACTIONt_gen_planes807HARMONIC5
X-RAY DIFFRACTIONt_it5336HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion718SEMIHARMONIC5
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_contact5919SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d5336HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg7275HARMONIC21.2
X-RAY DIFFRACTIONt_omega_torsion3.71
X-RAY DIFFRACTIONt_other_torsion17.04
LS refinement shellResolution: 2.4→2.47 Å / Total num. of bins used: 18
RfactorNum. reflection% reflection
Rfree0.2583 112 4.03 %
Rwork0.2589 2664 -
all0.2589 2776 -
obs--95.11 %

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