7OVD

Human soluble adenylyl cyclase in complex with the inhibitor TDI10229

  • Classification: SIGNALING PROTEIN
  • Organism(s): Homo sapiens
  • Expression System: Trichoplusia ni
  • Mutation(s): No 

  • Deposited: 2021-06-14 Released: 2021-10-06 
  • Deposition Author(s): Steegborn, C., Quast, J.
  • Funding Organization(s): German Research Foundation (DFG), National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.243 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.201 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history. 


Literature

Discovery of TDI-10229: A Potent and Orally Bioavailable Inhibitor of Soluble Adenylyl Cyclase (sAC, ADCY10).

Fushimi, M., Buck, H., Balbach, M., Gorovyy, A., Ferreira, J., Rossetti, T., Kaur, N., Levin, L.R., Buck, J., Quast, J., van den Heuvel, J., Steegborn, C., Finkin-Groner, E., Kargman, S., Michino, M., Foley, M.A., Miller, M., Liverton, N.J., Huggins, D.J., Meinke, P.T.

(2021) ACS Med Chem Lett 12: 1283-1287

  • DOI: https://doi.org/10.1021/acsmedchemlett.1c00273
  • Primary Citation of Related Structures:  
    7OVD

  • PubMed Abstract: 

    Soluble adenylyl cyclase (sAC) has gained attention as a potential therapeutic target given the role of this enzyme in intracellular signaling. We describe successful efforts to design improved sAC inhibitors amenable for in vivo interrogation of sAC inhibition to assess its potential therapeutic applications. This work culminated in the identification of TDI-10229 ( 12 ), which displays nanomolar inhibition of sAC in both biochemical and cellular assays and exhibits mouse pharmacokinetic properties sufficient to warrant its use as an in vivo tool compound.

    • Organizational Affiliation: 

    Tri-Institutional Therapeutics Discovery Institute, New York, New York 10021, United States.


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Adenylate cyclase type 10475Homo sapiensMutation(s): 0 
Gene Names: ADCY10, SAC
EC: 4.6.1.1
UniProt & NIH Common Fund Data Resources
Find proteins for Q96PN6 (Homo sapiens)
Explore Q96PN6 
Go to UniProtKB:  Q96PN6
PHAROS:  Q96PN6
GTEx:  ENSG00000143199 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ96PN6
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1S2 (Subject of Investigation/LOI)
Query on 1S2
Download Ideal Coordinates CCD File 
B [auth A]4-chloranyl-6-[1,5-dimethyl-4-(phenylmethyl)pyrazol-3-yl]pyrimidin-2-amine
C16 H16 Cl N5
VSMTYSWGHKYXOF-UHFFFAOYSA-N
DMS
Query on DMS
Download Ideal Coordinates CCD File 
D [auth A],
E [auth A],
F [auth A],
L [auth A]		DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
EDO
Query on EDO
Download Ideal Coordinates CCD File 
G [auth A]
H [auth A]
K [auth A]
M [auth A]
N [auth A]
G [auth A],
H [auth A],
K [auth A],
M [auth A],
N [auth A],
O [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
ACT
Query on ACT
Download Ideal Coordinates CCD File 
C [auth A],
I [auth A],
J [auth A],
P [auth A]		ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
CME
Query on CME
A
L-PEPTIDE LINKINGC5 H11 N O3 S2CYS
Binding Affinity Annotations 
IDSourceBinding Affinity
1S2 BindingDB:  7OVD Kd: 176 (nM) from 1 assay(s)
IC50: min: 92, max: 195 (nM) from 4 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.243 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.201 
  • Space Group: P 63
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 99.177α = 90
b = 99.177β = 90
c = 99.593γ = 120
Software Package:
Software NamePurpose
Cootmodel building
PHENIXrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


View more in-depth experimental data
Entry History & Funding Information

Deposition Data

Funding OrganizationLocationGrant Number
German Research Foundation (DFG)GermanySTE1701/11
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)United StatesP50 HD100549

Revision History  (Full details and data files)

  • Version 1.0: 2021-10-06
    Type: Initial release
  • Version 1.1: 2024-01-31
    Changes: Data collection, Refinement description
  • Version 1.2: 2024-10-16
    Changes: Structure summary