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- PDB-3q5h: Clinically Useful Alkyl Amine Renin Inhibitors -

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Basic information

Entry
Database: PDB / ID: 3q5h
TitleClinically Useful Alkyl Amine Renin Inhibitors
ComponentsRenin
KeywordsHYDROLASE/HYDROLASE INHIBITOR / aspartate protease / hypertension / renin expression / renin inhibitor / aspartyl protease / cleavage on pair of basic residues / disease mutation / glycoprotein / membrane / protease / secreted / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


renin / mesonephros development / juxtaglomerular apparatus development / response to cGMP / renin-angiotensin regulation of aldosterone production / drinking behavior / response to immobilization stress / regulation of MAPK cascade / response to cAMP / amyloid-beta metabolic process ...renin / mesonephros development / juxtaglomerular apparatus development / response to cGMP / renin-angiotensin regulation of aldosterone production / drinking behavior / response to immobilization stress / regulation of MAPK cascade / response to cAMP / amyloid-beta metabolic process / Metabolism of Angiotensinogen to Angiotensins / cell maturation / angiotensin maturation / hormone-mediated signaling pathway / insulin-like growth factor receptor binding / 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: 2.16 Å
AuthorsWu, Z. / McKeever, B.M.
CitationJournal: ACS Med Chem Lett / Year: 2011
Title: Discovery of VTP-27999, an Alkyl Amine Renin Inhibitor with Potential for Clinical Utility.
Authors: Jia, L. / Simpson, R.D. / Yuan, J. / Xu, Z. / Zhao, W. / Cacatian, S. / Tice, C.M. / Guo, J. / Ishchenko, A. / Singh, S.B. / Wu, Z. / McKeever, B.M. / Bukhtiyarov, Y. / Johnson, J.A. / Doe, ...Authors: Jia, L. / Simpson, R.D. / Yuan, J. / Xu, Z. / Zhao, W. / Cacatian, S. / Tice, C.M. / Guo, J. / Ishchenko, A. / Singh, S.B. / Wu, Z. / McKeever, B.M. / Bukhtiyarov, Y. / Johnson, J.A. / Doe, C.P. / Harrison, R.K. / McGeehan, G.M. / Dillard, L.W. / Baldwin, J.J. / Claremon, D.A.
History
DepositionDec 28, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 30, 2011Provider: repository / Type: Initial release
Revision 1.1Sep 24, 2014Group: Database references
Revision 1.2Jul 17, 2019Group: Data collection / Derived calculations / Refinement description
Category: software / struct_conn
Item: _software.classification / _software.name ..._software.classification / _software.name / _software.version / _struct_conn.pdbx_leaving_atom_flag
Revision 2.0Jul 29, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / pdbx_validate_close_contact / struct_asym / struct_conn / struct_site / struct_site_gen
Item: _atom_site.auth_asym_id / _atom_site.auth_seq_id ..._atom_site.auth_asym_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _chem_comp.name / _chem_comp.type / _entity.formula_weight / _entity.pdbx_description / _entity.pdbx_number_of_molecules / _entity.type / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_validate_close_contact.auth_asym_id_1 / _pdbx_validate_close_contact.auth_seq_id_1 / _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_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Sep 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
Revision 2.2Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)76,22111
Polymers74,5342
Non-polymers1,6879
Water3,027168
1
A: Renin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,3587
Polymers37,2671
Non-polymers1,0916
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Renin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,8634
Polymers37,2671
Non-polymers5963
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)54.650, 97.850, 149.006
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, renin / Plasmid: pcDNA3.1 / Cell line (production host): HEK 293 / Production host: Homo sapiens (human) / References: UniProt: P00797, renin
#2: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#3: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-RX6 / methyl (2-{(R)-(3-chlorophenyl)[(3R)-1-({(2S)-1-(methylamino)-3-[(3R)-tetrahydro-2H-pyran-3-yl]propan-2-yl}carbamoyl)piperidin-3-yl]methoxy}ethyl)carbamate


Mass: 525.081 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H41ClN4O5
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 168 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.67 Å3/Da / Density % sol: 53.98 %
Crystal growTemperature: 278 K / Method: vapor diffusion, hanging drop
Details: 0.1 M Tris-HCl, 0.2 M ammonium sulfate, 18-26% PEG3550, 5 mg/mL renin, 1 mm inhibitor, pH 7.0-8.0, VAPOR DIFFUSION, HANGING DROP, temperature 278K
PH range: 7.0-8.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X8C / Wavelength: 1.1
DetectorType: ADSC QUANTUM 4r / Detector: CCD / Date: Aug 4, 2006
RadiationMonochromator: Si (111) Double-crystal monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1 Å / Relative weight: 1
ReflectionResolution: 2.16→48.93 Å / Num. all: 43723 / Num. obs: 41821 / % possible obs: 95.6 % / Redundancy: 5 % / Rmerge(I) obs: 0.086 / Net I/σ(I): 18.31

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Processing

Software
NameVersionClassification
REFMAC5.5.0102refinement
CNSrefinement
CBASSdata collection
HKL-2000data reduction
HKL-2000data scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3GW5

3gw5


Resolution: 2.16→48.92 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.928 / SU B: 7.626 / SU ML: 0.188 / Cross valid method: THROUGHOUT / ESU R: 0.279 / ESU R Free: 0.223 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.26839 2099 5 %RANDOM
Rwork0.2239 ---
obs0.22619 39698 95.76 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 42.456 Å2
Baniso -1Baniso -2Baniso -3
1--0.03 Å20 Å20 Å2
2--0.01 Å20 Å2
3---0.02 Å2
Refinement stepCycle: LAST / Resolution: 2.16→48.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5204 0 106 168 5478
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.020.0225469
X-RAY DIFFRACTIONr_angle_refined_deg1.9531.9827419
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.9665669
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.04924.196224
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.88715864
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.4331520
X-RAY DIFFRACTIONr_chiral_restr0.1290.2839
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0214079
X-RAY DIFFRACTIONr_mcbond_it1.0991.53329
X-RAY DIFFRACTIONr_mcangle_it2.01925376
X-RAY DIFFRACTIONr_scbond_it3.00232140
X-RAY DIFFRACTIONr_scangle_it4.784.52043
LS refinement shellResolution: 2.161→2.217 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.47 106 -
Rwork0.356 2179 -
obs--72.13 %

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