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- PDB-5kot: Discovery of TAK-272: A Novel, Potent and Orally Active Renin In-... -

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Basic information

Entry
Database: PDB / ID: 5kot
TitleDiscovery of TAK-272: A Novel, Potent and Orally Active Renin In-hibitor
ComponentsRenin
KeywordsHYDROLASE/HYDROLASE inhibitor / protein-inhibitor complex / 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
Chem-6VU / DI(HYDROXYETHYL)ETHER / TRIETHYLENE GLYCOL / Renin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.1 Å
AuthorsSnell, G.P. / Behnke, C.A. / Okada, K. / Hideyuki, O. / Sang, B.-C. / Lane, W.
CitationJournal: To be published
Title: Discovery of TAK-272: A Novel, Potent and Orally Active Renin Inhibitor
Authors: Imaeda, Y. / Tokuhara, H. / Fukase, Y. / Kanagawa, R. / Kajimoto, Y. / Kusumoto, K. / Kondo, M. / Snell, G.P. / Behnke, C.A. / Kuroita, T.
History
DepositionJul 1, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 5, 2017Provider: repository / Type: Initial release
Revision 1.1Jul 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

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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)77,14026
Polymers73,8792
Non-polymers3,26024
Water5,224290
1
A: Renin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,75415
Polymers36,9401
Non-polymers1,81414
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Renin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,38611
Polymers36,9401
Non-polymers1,44610
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)231,41978
Polymers221,6386
Non-polymers9,78172
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation5_555z,x,y1
crystal symmetry operation9_555y,z,x1
Buried area13070 Å2
ΔGint-64 kcal/mol
Surface area69030 Å2
MethodPISA
Unit cell
Length a, b, c (Å)139.317, 139.317, 139.317
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number198
Space group name H-MP213

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Components

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Protein / Sugars , 2 types, 4 molecules AB

#1: Protein Renin / / Angiotensinogenase


Mass: 36939.594 Da / Num. of mol.: 2 / Fragment: UNP residues 70-406
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: REN / Cell line (production host): HEK 293 / Production host: Homo sapiens (human) / References: UniProt: P00797, renin
#2: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine


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

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Non-polymers , 5 types, 312 molecules

#3: Chemical ChemComp-6VU / 1-(4-methoxybutyl)-~{N}-(2-methylpropyl)-~{N}-[(3~{S},5~{R})-5-morpholin-4-ylcarbonylpiperidin-3-yl]benzimidazole-2-carboxamide


Mass: 499.646 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H41N5O4
#4: Chemical ChemComp-PGE / TRIETHYLENE GLYCOL / Polyethylene glycol


Mass: 150.173 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H14O4
#5: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C4H10O3
#6: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 14 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 290 / 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: 3.06 Å3/Da / Density % sol: 59.75 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.9
Details: 23% PEG600, 100 mM citrate, Buffer: 25 mM Tris pH 7.9, 150 mM NaCl, Ligand was soaked for 18h at 2mM

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 4r / Detector: CCD / Date: Feb 29, 2008
RadiationMonochromator: Si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→50 Å / Num. obs: 52521 / % possible obs: 100 % / Redundancy: 7 % / Rmerge(I) obs: 0.076 / Χ2: 0.997 / Net I/av σ(I): 21.276 / Net I/σ(I): 9.8 / Num. measured all: 365276
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
2.1-2.156.30.7651100
2.15-2.26.60.6611100
2.2-2.266.70.531100
2.26-2.336.70.4451100
2.33-2.46.80.3831100
2.4-2.496.90.3321100
2.49-2.596.90.261100
2.59-2.7170.1991100
2.71-2.857.20.161100
2.85-3.037.30.121100
3.03-3.267.30.0961100
3.26-3.597.10.0721100
3.59-4.117.20.0561100
4.11-5.187.20.0431100
5.18-507.10.032199.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
HKL-2000data scaling
MOLREPphasing
REFMAC5.8.0135refinement
PDB_EXTRACT3.2data extraction
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→50 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.951 / SU B: 7.688 / SU ML: 0.104 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.171 / ESU R Free: 0.146
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2027 2669 5.1 %RANDOM
Rwork0.1771 ---
obs0.1784 49705 99.77 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 89.33 Å2 / Biso mean: 44.13 Å2 / Biso min: 24.65 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: final / Resolution: 2.1→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5053 0 204 290 5547
Biso mean--52.13 53.05 -
Num. residues----665
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0195412
X-RAY DIFFRACTIONr_bond_other_d0.0020.024929
X-RAY DIFFRACTIONr_angle_refined_deg1.3321.9797328
X-RAY DIFFRACTIONr_angle_other_deg0.868311355
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.1265675
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.75724.393214
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.25415813
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.0671515
X-RAY DIFFRACTIONr_chiral_restr0.0720.2829
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.026020
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021199
X-RAY DIFFRACTIONr_mcbond_it0.9492.6642670
X-RAY DIFFRACTIONr_mcbond_other0.9442.6632669
X-RAY DIFFRACTIONr_mcangle_it1.5153.9893334
LS refinement shellResolution: 2.103→2.158 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.233 188 -
Rwork0.221 3633 -
all-3821 -
obs--99.82 %
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)
11.2220.10360.05761.99610.70193.32520.0077-0.0699-0.18350.1083-0.0189-0.10770.31210.02310.01120.0430.00380.0190.00480.01520.0656-21.441-46.6255-16.5997
22.2219-2.1622-1.855810.17046.01417.4812-0.0595-0.0928-0.10010.2302-0.3040.64320.4795-0.49190.36350.0684-0.00770.00840.12130.01040.0861-32.0981-39.9884-19.3412
32.0178-0.58950.56754.50820.13592.8666-0.0712-0.38420.05270.4190.03050.08430.0366-0.29190.04070.0756-0.00210.00880.16930.01110.0112-25.5685-36.27534.5955
46.34381.05780.96973.5373-0.52784.137-0.29660.2180.7021-0.16730.12750.0035-0.78170.08560.16910.27560.0436-0.08770.0877-0.00110.1781-20.0099-16.2575-1.9403
51.92182.49451.55966.196-0.35685.9045-0.15940.0541-0.0439-0.37340.11060.14190.1878-0.15660.04880.1550.01820.00450.2544-0.010.2199-38.419-33.976-5.6743
63.2032-0.6077-0.60672.8924-1.04082.595-0.0843-0.2486-0.08240.37430.18920.3427-0.184-0.4245-0.10490.1210.08190.02830.1882-0.00160.0596-12.5079-24.583123.5488
79.35061.8925-6.02930.9785-1.14343.99840.1217-0.27890.11340.4424-0.1105-0-0.18920.0377-0.01130.5690.166-0.09070.2277-0.11620.1266-8.3784-14.840129.5149
82.5052-0.107-0.75774.5513-1.6332.60570.02410.11080.0119-0.0521-0.2108-0.4823-0.12740.21810.18670.0520.0459-0.01280.12560.02410.09859.5157-24.665614.301
93.48040.2323-0.17017.2979-3.8646.53460.10420.09480.3896-0.3318-0.05780.0956-0.3-0.2859-0.04630.17690.05460.02120.23790.12420.21997.0678-8.2198-0.2815
102.0429-1.6813-2.17073.9162-2.39549.2261-0.1233-0.1662-0.0580.32830.22930.1722-0.227-0.0201-0.10590.2892-0.0202-0.03740.2517-0.01380.2548.7539-13.250826.6849
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A4 - 78
2X-RAY DIFFRACTION1A92 - 154
3X-RAY DIFFRACTION2A79 - 91
4X-RAY DIFFRACTION3A155 - 248
5X-RAY DIFFRACTION3A266 - 280
6X-RAY DIFFRACTION3A299 - 302
7X-RAY DIFFRACTION3A313 - 340
8X-RAY DIFFRACTION4A249 - 265
9X-RAY DIFFRACTION4A281 - 298
10X-RAY DIFFRACTION5A303 - 312
11X-RAY DIFFRACTION6B4 - 78
12X-RAY DIFFRACTION6B92 - 154
13X-RAY DIFFRACTION7B79 - 91
14X-RAY DIFFRACTION8B155 - 248
15X-RAY DIFFRACTION8B266 - 280
16X-RAY DIFFRACTION8B299 - 302
17X-RAY DIFFRACTION8B313 - 340
18X-RAY DIFFRACTION9B249 - 265
19X-RAY DIFFRACTION9B281 - 298
20X-RAY DIFFRACTION10B303 - 312

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