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- PDB-8b75: CRYSTAL STRUCTURE OF HUMAN SOLUBLE ADENYLYL CYCLASE IN COMPLEX WI... -

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Basic information

Entry
Database: PDB / ID: 8b75
TitleCRYSTAL STRUCTURE OF HUMAN SOLUBLE ADENYLYL CYCLASE IN COMPLEX WITH THE INHIBITOR TDI-011861
ComponentsAdenylate cyclase type 10
KeywordsSIGNALING PROTEIN / SOLUBLE ADENYLYL CYCLASE / ADCY10 / SIGNALING ENZYME / CLASS III CYCLASE
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
Chem-PJU / Adenylate cyclase type 10
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.82 Å
AuthorsSteegborn, C. / Kehr, M.
Funding support Germany, United States, 2items
OrganizationGrant numberCountry
German Research Foundation (DFG) Germany
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD) United States
CitationJournal: J.Med.Chem. / Year: 2022
Title: Design, Synthesis, and Pharmacological Evaluation of Second-Generation Soluble Adenylyl Cyclase (sAC, ADCY10) Inhibitors with Slow Dissociation Rates.
Authors: Miller, M. / Rossetti, T. / Ferreira, J. / Ghanem, L. / Balbach, M. / Kaur, N. / Levin, L.R. / Buck, J. / Kehr, M. / Coquille, S. / van den Heuvel, J. / Steegborn, C. / Fushimi, M. / Finkin- ...Authors: Miller, M. / Rossetti, T. / Ferreira, J. / Ghanem, L. / Balbach, M. / Kaur, N. / Levin, L.R. / Buck, J. / Kehr, M. / Coquille, S. / van den Heuvel, J. / Steegborn, C. / Fushimi, M. / Finkin-Groner, E. / Myers, R.W. / Kargman, S. / Liverton, N.J. / Huggins, D.J. / Meinke, P.T.
History
DepositionSep 28, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 29, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)54,7652
Polymers54,2701
Non-polymers4951
Water5,477304
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area21130 Å2
2
A: Adenylate cyclase type 10
hetero molecules

A: Adenylate cyclase type 10
hetero molecules

A: Adenylate cyclase type 10
hetero molecules


Theoretical massNumber of molelcules
Total (without water)164,2946
Polymers162,8093
Non-polymers1,4853
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_545-y,x-y-1,z1
crystal symmetry operation3_655-x+y+1,-x,z1
Buried area7640 Å2
ΔGint-44 kcal/mol
Surface area55740 Å2
MethodPISA
Unit cell
Length a, b, c (Å)100.131, 100.131, 97.889
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number173
Space group name H-MP63
Components on special symmetry positions
IDModelComponents
11A-897-

HOH

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Components

#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: Trichoplusia ni (cabbage looper) / References: UniProt: Q96PN6, adenylate cyclase
#2: Chemical ChemComp-PJU / [(3~{R})-4-[2-[2-[[3-(2-azanyl-6-chloranyl-pyrimidin-4-yl)-1-[bis(fluoranyl)methyl]pyrazol-4-yl]methyl]phenoxy]ethyl]morpholin-3-yl]methanol


Mass: 494.922 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H25ClF2N6O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 304 / Source method: isolated from a natural source / Formula: H2O
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: 2.61 Å3/Da / Density % sol: 52.88 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 0.1 M sodiumacetate, 0.2 M trisodiumcitrate, 15% PEG4000, 10% Glycerol, 277 K

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jul 20, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.82→48.944 Å / Num. obs: 47921 / % possible obs: 96 % / Redundancy: 8.44 % / Biso Wilson estimate: 31.513 Å2 / CC1/2: 0.994 / Rmerge(I) obs: 0.204 / Rrim(I) all: 0.216 / Net I/σ(I): 6.78
Reflection shellResolution: 1.82→1.93 Å / Redundancy: 2.42 % / Rmerge(I) obs: 1.814 / Mean I/σ(I) obs: 0.29 / Num. unique obs: 15090 / CC1/2: 0.14 / Rrim(I) all: 2.24 / % possible all: 77.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0352refinement
XDSdata reduction
pointlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4CLF

4clf


Resolution: 1.82→48.944 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.938 / SU B: 5.915 / SU ML: 0.155 / Cross valid method: FREE R-VALUE / ESU R: 0.143 / ESU R Free: 0.138
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2457 2098 4.382 %
Rwork0.2027 45785 -
all0.205 --
obs-47883 95.875 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 32.338 Å2
Baniso -1Baniso -2Baniso -3
1-0.299 Å20.15 Å20 Å2
2--0.299 Å2-0 Å2
3----0.971 Å2
Refinement stepCycle: LAST / Resolution: 1.82→48.944 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3677 0 34 304 4015
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0123950
X-RAY DIFFRACTIONr_bond_other_d0.0010.0163629
X-RAY DIFFRACTIONr_angle_refined_deg1.4311.6545387
X-RAY DIFFRACTIONr_angle_other_deg0.5161.5658447
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8795513
X-RAY DIFFRACTIONr_dihedral_angle_2_deg4.543514
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.90810685
X-RAY DIFFRACTIONr_dihedral_angle_6_deg15.31310175
X-RAY DIFFRACTIONr_chiral_restr0.0680.2601
X-RAY DIFFRACTIONr_chiral_restr_other2.2680.21
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.024462
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02783
X-RAY DIFFRACTIONr_nbd_refined0.2330.2748
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1930.23364
X-RAY DIFFRACTIONr_nbtor_refined0.1780.21902
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0810.22072
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1740.2245
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.1820.22
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.280.236
X-RAY DIFFRACTIONr_nbd_other0.2250.2101
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2260.227
X-RAY DIFFRACTIONr_mcbond_it2.9293.5191919
X-RAY DIFFRACTIONr_mcbond_other2.9273.5191919
X-RAY DIFFRACTIONr_mcangle_it4.6325.2622409
X-RAY DIFFRACTIONr_mcangle_other4.6335.2632410
X-RAY DIFFRACTIONr_scbond_it3.33.7132031
X-RAY DIFFRACTIONr_scbond_other3.2993.7132032
X-RAY DIFFRACTIONr_scangle_it5.0795.462955
X-RAY DIFFRACTIONr_scangle_other5.0785.4592956
X-RAY DIFFRACTIONr_lrange_it7.98253.9344491
X-RAY DIFFRACTIONr_lrange_other7.94651.1574405
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
1.82-1.8670.4221070.4123470.4136710.8130.81866.84830.419
1.867-1.9180.4031330.3929020.3935850.7050.70784.65830.395
1.918-1.9730.3511440.36331410.36335070.9170.90193.66980.367
1.973-2.0340.3671440.34731550.34833500.8990.9198.47760.354
2.034-2.1010.3021430.29431070.29432630.9360.93899.60160.295
2.101-2.1740.3411410.26530720.26832150.9220.95399.93780.258
2.174-2.2560.2831340.22629240.22830580.9460.9671000.214
2.256-2.3480.2561280.20428070.20629350.9610.9741000.187
2.348-2.4520.3031260.20127380.20628640.9480.9751000.179
2.452-2.5720.2721180.1925760.19326940.9520.9781000.166
2.572-2.710.1991130.18524720.18625850.9740.9791000.164
2.71-2.8740.2421060.18423230.18624290.9660.981000.162
2.874-3.0720.2351010.18621880.18822890.9690.981000.166
3.072-3.3170.239940.19220540.19421480.9670.9791000.177
3.317-3.6320.206860.16918870.17119730.9750.9851000.161
3.632-4.0580.187780.15617050.15817830.9770.9871000.15
4.058-4.680.186700.13215210.13415910.9810.9891000.13
4.68-5.7190.186590.14712740.14913330.9840.9891000.142
5.719-8.0330.262460.21210100.21410560.9590.9781000.198
8.033-48.9440.255270.1975810.1996100.9540.97499.67210.21

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