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- PDB-8cot: Complex of human soluble adenylyl cyclase 10 catalytic core with ... -

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Basic information

Entry
Database: PDB / ID: 8cot
TitleComplex of human soluble adenylyl cyclase 10 catalytic core with inhibitor TDI-10962
ComponentsAdenylate cyclase type 10
KeywordsSIGNALING PROTEIN / cAMP / sAC / inhibitor complex
Function / homology
Function and homology information


negative regulation of cardiac muscle cell contraction / astrocyte end-foot / mitochondrial ATP transmembrane transport / epithelial cilium movement involved in extracellular fluid movement / bicarbonate binding / neuron projection retraction / positive regulation of glycogen catabolic process / central region of growth cone / cellular response to inorganic substance / regulation of mitophagy ...negative regulation of cardiac muscle cell contraction / astrocyte end-foot / mitochondrial ATP transmembrane transport / epithelial cilium movement involved in extracellular fluid movement / bicarbonate binding / neuron projection retraction / positive regulation of glycogen catabolic process / central region of growth cone / cellular response to inorganic substance / regulation of mitophagy / glucose catabolic process / regulation of membrane repolarization / adenylate cyclase / basal part of cell / positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cAMP biosynthetic process / positive regulation of ossification / adenylate cyclase activity / positive regulation of protein targeting to mitochondrion / positive regulation of reactive oxygen species biosynthetic process / neuron projection extension / positive regulation of vascular associated smooth muscle cell apoptotic process / positive regulation of mitochondrial depolarization / positive regulation of ATP biosynthetic process / positive regulation of cardiac muscle hypertrophy / positive regulation of cardiac muscle cell apoptotic process / spermatid development / negative regulation of mitochondrial membrane potential / positive regulation of axon extension / Hedgehog 'off' state / negative regulation of reactive oxygen species biosynthetic process / neuron projection maintenance / positive regulation of peptidyl-threonine phosphorylation / cilium / manganese ion binding / ATPase binding / cytoskeleton / intracellular signal transduction / apical plasma membrane / neuronal cell body / dendrite / perinuclear region of cytoplasm / magnesium ion binding / mitochondrion / extracellular region / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Adenylate cyclase, type 10 / Adenylyl cyclase class-3/4/guanylyl cyclase / Adenylate and Guanylate cyclase catalytic domain / Guanylate cyclase domain profile. / Nucleotide cyclase / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
ACETATE ION / Chem-VBB / Adenylate cyclase type 10
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsSteegborn, C. / Fushimi, M.
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research Foundation (DFG)STE1701/11 Germany
CitationJournal: J.Chem.Inf.Model. / Year: 2023
Title: Scaffold Hopping and Optimization of Small Molecule Soluble Adenyl Cyclase Inhibitors Led by Free Energy Perturbation.
Authors: Sun, S. / Fushimi, M. / Rossetti, T. / Kaur, N. / Ferreira, J. / Miller, M. / Quast, J. / van den Heuvel, J. / Steegborn, C. / Levin, L.R. / Buck, J. / Myers, R.W. / Kargman, S. / Liverton, ...Authors: Sun, S. / Fushimi, M. / Rossetti, T. / Kaur, N. / Ferreira, J. / Miller, M. / Quast, J. / van den Heuvel, J. / Steegborn, C. / Levin, L.R. / Buck, J. / Myers, R.W. / Kargman, S. / Liverton, N. / Meinke, P.T. / Huggins, D.J.
History
DepositionFeb 28, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 26, 2023Provider: repository / Type: Initial release
Revision 1.1May 17, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Adenylate cyclase type 10
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,54115
Polymers54,2701
Non-polymers1,27114
Water2,216123
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2860 Å2
ΔGint19 kcal/mol
Surface area19800 Å2
Unit cell
Length a, b, c (Å)99.314, 99.314, 98.854
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number173
Space group name H-MP63
Symmetry operation#1: x,y,z
#2: x-y,x,z+1/2
#3: y,-x+y,z+1/2
#4: -y,x-y,z
#5: -x+y,-x,z
#6: -x,-y,z+1/2
Components on special symmetry positions
IDModelComponents
11A-723-

HOH

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Adenylate cyclase type 10 / AH-related protein / Adenylate cyclase homolog / Germ cell soluble adenylyl cyclase / sAC / ...AH-related protein / Adenylate cyclase homolog / Germ cell soluble adenylyl cyclase / sAC / Testicular soluble adenylyl cyclase


Mass: 54269.664 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ADCY10, SAC / Production host: Escherichia coli (E. coli) / References: UniProt: Q96PN6, adenylate cyclase

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Non-polymers , 5 types, 137 molecules

#2: Chemical ChemComp-VBB / 2-(dimethylamino)ethyl 5-(2-azanyl-6-chloranyl-pyrimidin-4-yl)-2-methyl-4-(phenylmethyl)pyrazole-3-carboxylate


Mass: 414.889 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H23ClN6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical
ChemComp-ACT / ACETATE ION / Acetate


Mass: 59.044 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H3O2
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 123 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 2.59 Å3/Da / Density % sol: 52.57 %
Crystal growTemperature: 277 K / Method: vapor diffusion / Details: 0.2 M tripotassium citrate, 20%(w/v) PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.98 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 20, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.1→28.67 Å / Num. obs: 32328 / % possible obs: 99.8 % / Redundancy: 8.3 % / Biso Wilson estimate: 40.58 Å2 / CC1/2: 0.998 / Rrim(I) all: 0.138 / Net I/σ(I): 13.6
Reflection shellResolution: 2.1→2.17 Å / Num. unique obs: 3183 / CC1/2: 0.27

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Processing

Software
NameVersionClassification
PHENIX1.16_3549refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→28.67 Å / SU ML: 0.29 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 24.83 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2318 1617 5 %
Rwork0.192 --
obs0.1939 32312 99.79 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.1→28.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3585 0 81 123 3789
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0063808
X-RAY DIFFRACTIONf_angle_d0.9125149
X-RAY DIFFRACTIONf_dihedral_angle_d6.0913074
X-RAY DIFFRACTIONf_chiral_restr0.05566
X-RAY DIFFRACTIONf_plane_restr0.006658
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.16130.35461330.32572522X-RAY DIFFRACTION98
2.1613-2.2310.28151330.28892535X-RAY DIFFRACTION100
2.231-2.31070.30841350.26322555X-RAY DIFFRACTION100
2.3107-2.40330.3021340.25722552X-RAY DIFFRACTION100
2.4033-2.51260.27391340.23072551X-RAY DIFFRACTION100
2.5126-2.64510.23711360.22712571X-RAY DIFFRACTION100
2.6451-2.81080.29161340.21832552X-RAY DIFFRACTION100
2.8108-3.02770.30331340.20972549X-RAY DIFFRACTION100
3.0277-3.33230.21551350.19312570X-RAY DIFFRACTION100
3.3323-3.81430.19581360.17292575X-RAY DIFFRACTION100
3.8143-4.80460.20031350.13982560X-RAY DIFFRACTION100
4.8046-28.670.20191380.17812603X-RAY DIFFRACTION99
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)
10.6539-0.5248-0.10330.3519-0.02430.5644-0.0013-0.059-0.13710.13670.01440.00970.0433-0.001900.31620.0078-0.01370.29270.01450.3408-37.342412.0413.56
20.9713-0.40840.07051.2407-0.52061.795-0.0507-0.1082-0.03640.02360.1141-0.02310.28770.015-0.00010.36150.0097-0.04670.26950.0190.2928-31.34766.53311.5137
30.06230.0621-0.12291.50341.04221.3324-0.03180.1091-0.0733-0.0433-0.01870.02540.13020.01810.00020.32160.04740.01860.337-0.01350.3166-30.71132.1484-15.2693
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 7 through 88 )
2X-RAY DIFFRACTION2chain 'A' and (resid 89 through 287 )
3X-RAY DIFFRACTION3chain 'A' and (resid 288 through 468 )

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