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- PDB-1r4l: Inhibitor Bound Human Angiotensin Converting Enzyme-Related Carbo... -

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Basic information

Entry
Database: PDB / ID: 1r4l
TitleInhibitor Bound Human Angiotensin Converting Enzyme-Related Carboxypeptidase (ACE2)
Components
  • (disordered segment of collectrin homology ...) x 4
  • angiotensin I converting enzyme 2
KeywordsHYDROLASE / zinc metallopeptidase domain / collectrin homology domain / inhibitor bound conformation / chloride ion binding site / zinc ion binding site
Function / homology
Function and homology information


positive regulation of amino acid transport / angiotensin-converting enzyme 2 / positive regulation of L-proline import across plasma membrane / angiotensin-mediated drinking behavior / Hydrolases; Acting on peptide bonds (peptidases); Metallocarboxypeptidases / regulation of systemic arterial blood pressure by renin-angiotensin / positive regulation of gap junction assembly / tryptophan transport / regulation of cardiac conduction / regulation of vasoconstriction ...positive regulation of amino acid transport / angiotensin-converting enzyme 2 / positive regulation of L-proline import across plasma membrane / angiotensin-mediated drinking behavior / Hydrolases; Acting on peptide bonds (peptidases); Metallocarboxypeptidases / regulation of systemic arterial blood pressure by renin-angiotensin / positive regulation of gap junction assembly / tryptophan transport / regulation of cardiac conduction / regulation of vasoconstriction / peptidyl-dipeptidase activity / maternal process involved in female pregnancy / Metabolism of Angiotensinogen to Angiotensins / carboxypeptidase activity / angiotensin maturation / receptor-mediated endocytosis of virus by host cell / Attachment and Entry / metallocarboxypeptidase activity / viral life cycle / positive regulation of cardiac muscle contraction / regulation of cytokine production / regulation of transmembrane transporter activity / blood vessel diameter maintenance / negative regulation of smooth muscle cell proliferation / brush border membrane / negative regulation of ERK1 and ERK2 cascade / metallopeptidase activity / positive regulation of reactive oxygen species metabolic process / endocytic vesicle membrane / regulation of cell population proliferation / virus receptor activity / regulation of inflammatory response / endopeptidase activity / Potential therapeutics for SARS / Induction of Cell-Cell Fusion / entry receptor-mediated virion attachment to host cell / membrane fusion / Attachment and Entry / receptor-mediated virion attachment to host cell / cilium / apical plasma membrane / membrane raft / endoplasmic reticulum lumen / symbiont entry into host cell / cell surface / extracellular space / extracellular exosome / extracellular region / zinc ion binding / identical protein binding / membrane / plasma membrane
Similarity search - Function
Collectrin domain / Renal amino acid transporter / Collectrin-like domain profile. / Peptidase M2, peptidyl-dipeptidase A / Angiotensin-converting enzyme / Peptidase family M2 domain profile. / Neutral zinc metallopeptidases, zinc-binding region signature.
Similarity search - Domain/homology
Chem-XX5 / Angiotensin-converting enzyme 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsTowler, P. / Staker, B. / Prasad, S.G. / Menon, S. / Ryan, D. / Tang, J. / Parsons, T. / Fisher, M. / Williams, D. / Dales, N.A. ...Towler, P. / Staker, B. / Prasad, S.G. / Menon, S. / Ryan, D. / Tang, J. / Parsons, T. / Fisher, M. / Williams, D. / Dales, N.A. / Patane, M.A. / Pantoliano, M.W.
Citation
Journal: J.Biol.Chem. / Year: 2004
Title: ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis.
Authors: Towler, P. / Staker, B. / Prasad, S.G. / Menon, S. / Tang, J. / Parsons, T. / Ryan, D. / Fisher, M. / Williams, D. / Dales, N.A. / Patane, M.A. / Pantoliano, M.W.
#1: Journal: J.Am.Chem.Soc. / Year: 2002
Title: Substrate Based Design of the First Class of Angiotensin-Converting Enzyme-Related Carboxypeptidase (ACE2) Inhibitors
Authors: Dales, N. / Gould, A.E. / Brown, J.A. / Calderwood, E.F. / Guan, B. / Minor, C.A. / Gavin, J.M. / Hales, P. / Kaushik, V.K. / Stewart, M. / Tummino, P.J. / Vickers, C.S. / Ocain, T.D. / Patane, M.A.
#2: Journal: J.Biol.Chem. / Year: 2002
Title: Hydrolysis of Biological Peptides by Human Angiotensin-converting Enzyme-related Carboxypeptidase
Authors: Vickers, C. / Hales, P. / Kaushik, V. / Dick, L. / Gavin, J. / Tang, J. / Godbout, K. / Parsons, T. / Baronas, E. / Hsieh, F. / Acton, S. / Patane, M. / Nichols, A. / Tummino, P.
History
DepositionOct 7, 2003Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 3, 2004Provider: repository / Type: Initial release
Revision 1.1Apr 29, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Non-polymer description / Version format compliance
Revision 1.3Jul 29, 2020Group: Advisory / Data collection ...Advisory / Data collection / Derived calculations / Structure summary
Category: chem_comp / database_PDB_caveat ...chem_comp / database_PDB_caveat / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / pdbx_struct_conn_angle / 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 / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _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_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.4Aug 23, 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 1.5Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature
Remark 999SEQUENCE The complete sequence crystallized by the authors (residues 1-740 of reference sequence GB ...SEQUENCE The complete sequence crystallized by the authors (residues 1-740 of reference sequence GB 11225609) is as follows: MSSSSWLLLSLVAVTAAQSTIEEQAKTFLDKFNHEAEDLFYQSSLASWNY NTNITEENVQNMNNAGDKWSAFLKEQSTLAQMYPLQEIQNLTVKLQLQALQ QNGSSVLSEDKSKRLNTILNTMSTIYSTGKVCNPDNPQECLLLEPGLNEIM ANSLDYNERLWAWESWRSEVGKQLRPLYEEYVVLKNEMARANHYEDYGDYW RGDYEVNGVDGYDYSRGQLIEDVEHTFEEIKPLYEHLHAYVRAKLMNAYPS YISPIGCLPAHLLGDMWGRFWTNLYSLTVPFGQKPNIDVTDAMVDQAWDAQ RIFKEAEKFFVSVGLPNMTQGFWENSMLTDPGNVQKAVCHPTAWDLGKGDF RILMCTKVTMDDFLTAHHEMGHIQYDMAYAAQPFLLRNGANEGFHEAVGEI MSLSAATPKHLKSIGLLSPDFQEDNETEINFLLKQALTIVGTLPFTYMLEK WRWMVFKGEIPKDQWMKKWWEMKREIVGVVEPVPHDETYCDPASLFHVSND YSFIRYYTRTLYQFQFQEALCQAAKHEGPLHKCDISNSTEAGQKLFNMLRL GKSEPWTLALENVVGAKNMNVRPLLNYFEPLFTWLKDQNKNSFVGWSTDWS PYADQSIKVRISLKSALGDKAYEWNDNEMYLFRSSVAYAMRQYFLKVKNQ MILFGEEDVRVANLKPRISFNFFVTAPKNVSDIIPRTEVEKAIRMSRSRIN DAFRLNDNSLEFLGIQPTLGPPNQPPVS The electron density map for much of the collectrin homology domain (residues 616-740) is weak. Only about half of this domain was visible in the electron density map, and what can be seen is ambiguous due to topology and connectivity issues. For this reason, residues beginning at 901 are labeled as unknown (UNK). Each segment of unknown residues has been assigned a unique chain ID. However, it should be understood that only one sequence (residues 1-740) was crystallized.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: angiotensin I converting enzyme 2
B: disordered segment of collectrin homology domain
C: disordered segment of collectrin homology domain
D: disordered segment of collectrin homology domain
E: disordered segment of collectrin homology domain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,98010
Polymers76,0085
Non-polymers9725
Water23413
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)100.531, 86.509, 105.858
Angle α, β, γ (deg.)90.00, 103.65, 90.00
Int Tables number5
Space group name H-MC121

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Components

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Disordered segment of collectrin homology ... , 4 types, 4 molecules BCDE

#2: Protein/peptide disordered segment of collectrin homology domain


Mass: 528.644 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ACE2 / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm)
#3: Protein/peptide disordered segment of collectrin homology domain


Mass: 1720.111 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ACE2 / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm)
#4: Protein/peptide disordered segment of collectrin homology domain


Mass: 1549.902 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ACE2 / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm)
#5: Protein/peptide disordered segment of collectrin homology domain


Mass: 1209.482 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ACE2 / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm)

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Protein / Sugars , 2 types, 3 molecules A

#1: Protein angiotensin I converting enzyme 2 / angiotensin converting enzyme-like protein / Angiotensin Converting Enzyme-Related Carboxypeptidase


Mass: 70999.820 Da / Num. of mol.: 1 / Fragment: Extracellular domains
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ACE2 / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9BYF1
#6: 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

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Non-polymers , 4 types, 16 molecules

#7: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#8: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#9: Chemical ChemComp-XX5 / (S,S)-2-{1-CARBOXY-2-[3-(3,5-DICHLORO-BENZYL)-3H-IMIDAZOL-4-YL]-ETHYLAMINO}-4-METHYL-PENTANOIC ACID / MLN-4760


Mass: 428.310 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H23Cl2N3O4
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 13 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.94 Å3/Da / Density % sol: 58.18 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 19% PEG 3000, 100mM Tris-HCl, 600mM NaCl, pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 291K
Crystal grow
*PLUS
Temperature: 16-18 ℃ / Method: vapor diffusion, hanging drop
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDDetailsChemical formula
15.9 mg/mlprotein1drop
219 %PEG30001reservoir
3100 mMTris-HCl1reservoirpH7.5
4600 mM1reservoirNaCl

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X25
DetectorDetector: AREA DETECTOR
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 3→50 Å / Num. obs: 17526 / % possible obs: 95.9 % / Observed criterion σ(I): 0 / Biso Wilson estimate: 63 Å2 / Rsym value: 0.07 / Net I/σ(I): 13.2
Reflection shellResolution: 3→3.08 Å / Mean I/σ(I) obs: 2 / Rsym value: 0.23 / % possible all: 74.5
Reflection
*PLUS
Highest resolution: 3 Å / Lowest resolution: 43.3 Å / Num. obs: 17228 / % possible obs: 96.8 % / Rmerge(I) obs: 0.07
Reflection shell
*PLUS
Highest resolution: 3 Å / Lowest resolution: 3.19 Å / % possible obs: 85.1 % / Num. unique obs: 2250 / Rmerge(I) obs: 0.204

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Processing

Software
NameVersionClassification
CNX2002refinement
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1R42

1r42


Resolution: 3→43.26 Å / Rfactor Rfree error: 0.008 / Data cutoff high absF: 2938880.39 / Data cutoff high rms absF: 2938880.39 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.337 1730 10 %RANDOM
Rwork0.253 ---
obs-17228 96.8 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 56.626 Å2 / ksol: 0.304373 e/Å3
Displacement parametersBiso mean: 74.5 Å2
Baniso -1Baniso -2Baniso -3
1-20.07 Å20 Å220.3 Å2
2--15 Å20 Å2
3----35.07 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.56 Å0.39 Å
Luzzati d res low-5 Å
Luzzati sigma a0.74 Å0.62 Å
Refinement stepCycle: LAST / Resolution: 3→43.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5147 0 58 13 5218
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_angle_deg1.5
X-RAY DIFFRACTIONc_dihedral_angle_d22.2
X-RAY DIFFRACTIONc_improper_angle_d0.97
X-RAY DIFFRACTIONc_mcbond_it2.021.5
X-RAY DIFFRACTIONc_mcangle_it3.422
X-RAY DIFFRACTIONc_scbond_it2.752
X-RAY DIFFRACTIONc_scangle_it4.272.5
LS refinement shellResolution: 3→3.19 Å / Rfactor Rfree error: 0.029 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.46 247 9.9 %
Rwork0.379 2250 -
obs--85.1 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2XX5_PAR.PARAMXX5_TOP.TOP
X-RAY DIFFRACTION3WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION4ION.PARAMION.TOP
X-RAY DIFFRACTION5CARBOHYDRATE.PARAMCARBOHYDRATE.TOP
Refinement
*PLUS
Highest resolution: 3 Å / Lowest resolution: 43.3 Å / Num. reflection Rfree: 1723
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_deg22.2
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_deg0.97
LS refinement shell
*PLUS
Rfactor Rfree: 0.46

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