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

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Basic information

Entry
Database: PDB / ID: 5kos
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-6VS / DI(HYDROXYETHYL)ETHER / Renin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.41 Å
AuthorsSnell, G.P. / Behnke, C.A. / Okada, K. / Hideyuki, O. / Sang, B.-C. / Lane, W.
CitationJournal: Acs Med.Chem.Lett. / Year: 2016
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. / Behnke, C.A. / Kuroita, T.
History
DepositionJul 1, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 16, 2016Provider: 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 / pdbx_struct_oper_list / 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 / _pdbx_struct_oper_list.symmetry_operation
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)76,45919
Polymers73,8792
Non-polymers2,57917
Water3,765209
1
A: Renin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,51713
Polymers36,9401
Non-polymers1,57712
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Renin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,9426
Polymers36,9401
Non-polymers1,0025
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)229,37657
Polymers221,6386
Non-polymers7,73851
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation8_544-z,x-1/2,-y-1/21
crystal symmetry operation11_545y+1/2,-z-1/2,-x1
Buried area13420 Å2
ΔGint-63 kcal/mol
Surface area70310 Å2
MethodPISA
Unit cell
Length a, b, c (Å)137.077, 137.077, 137.077
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 , 4 types, 224 molecules

#3: Chemical ChemComp-6VS / 2-~{tert}-butyl-4-(3-methoxypropylamino)-~{N}-(2-methylpropyl)-~{N}-[(3~{S},5~{R})-5-morpholin-4-ylcarbonylpiperidin-3-yl]pyrimidine-5-carboxamide


Mass: 518.692 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H46N6O4
#4: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C4H10O3
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 209 / 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: 2.91 Å3/Da / Density % sol: 57.66 %
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 5mM

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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: Oct 25, 2007
RadiationMonochromator: Si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.4→50 Å / Num. obs: 33502 / % possible obs: 99.8 % / Redundancy: 6.1 % / Rmerge(I) obs: 0.099 / Χ2: 1.014 / Net I/av σ(I): 15.918 / Net I/σ(I): 8.8 / Num. measured all: 203475
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
2.4-2.465.90.7691100
2.46-2.526.10.7351100
2.52-2.596.20.6031100
2.59-2.666.20.4751100
2.66-2.756.20.4061100
2.75-2.856.20.3121100
2.85-2.966.20.2411100
2.96-3.096.20.1961100
3.09-3.266.20.1551100
3.26-3.466.10.1221100
3.46-3.7360.0921100
3.73-4.15.90.074199.9
4.1-4.75.80.054199.7
4.7-5.9260.048199.4
5.92-505.80.041198.2

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
HKL-2000data scaling
MOLREPphasing
PDB_EXTRACT3.2data extraction
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.41→50 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.93 / SU B: 14.246 / SU ML: 0.167 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.338 / ESU R Free: 0.234
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2298 1694 5.1 %RANDOM
Rwork0.1847 ---
obs0.1869 31736 99.65 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 100.94 Å2 / Biso mean: 47.926 Å2 / Biso min: 26.64 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: final / Resolution: 2.41→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5079 0 163 209 5451
Biso mean--56.83 49.03 -
Num. residues----663
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0195381
X-RAY DIFFRACTIONr_bond_other_d0.0020.024919
X-RAY DIFFRACTIONr_angle_refined_deg1.2821.9757287
X-RAY DIFFRACTIONr_angle_other_deg0.86311327
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.0055664
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.63924.055217
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.21115828
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.7411519
X-RAY DIFFRACTIONr_chiral_restr0.070.2820
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.025964
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021211
X-RAY DIFFRACTIONr_mcbond_it1.3023.1572653
X-RAY DIFFRACTIONr_mcbond_other1.2993.1562652
X-RAY DIFFRACTIONr_mcangle_it2.1684.7283309
LS refinement shellResolution: 2.406→2.469 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.306 109 -
Rwork0.237 2333 -
all-2442 -
obs--100 %
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)
10.78290.519-0.37963.131-1.17781.4645-0.01840.03280.1993-0.05590.13760.2175-0.0614-0.1395-0.11920.01110.0174-0.01240.0743-0.01690.06679.8372-39.63383.9356
22.7566-0.741-0.52022.05860.89662.23250.09710.25440.1423-0.22120.0178-0.0241-0.23920.0338-0.11490.0629-0.0147-0.02310.0330.02460.053333.2486-16.062-12.4636
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A4 - 78
2X-RAY DIFFRACTION1A79 - 91
3X-RAY DIFFRACTION1A92 - 154
4X-RAY DIFFRACTION1A155 - 248
5X-RAY DIFFRACTION1A249 - 265
6X-RAY DIFFRACTION1A266 - 280
7X-RAY DIFFRACTION1A281 - 298
8X-RAY DIFFRACTION1A299 - 302
9X-RAY DIFFRACTION1A303 - 312
10X-RAY DIFFRACTION1A313 - 340
11X-RAY DIFFRACTION2B4 - 78
12X-RAY DIFFRACTION2B79 - 91
13X-RAY DIFFRACTION2B92 - 154
14X-RAY DIFFRACTION2B155 - 248
15X-RAY DIFFRACTION2B249 - 265
16X-RAY DIFFRACTION2B266 - 280
17X-RAY DIFFRACTION2B281 - 298
18X-RAY DIFFRACTION2B299 - 302
19X-RAY DIFFRACTION2B303 - 312
20X-RAY DIFFRACTION2B313 - 340

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