9C1Y | pdb_00009c1y

Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in complex with 7-((3-(((4-(6-aminopyridin-2-yl)butyl)amino)methyl)phenoxy)methyl)quinolin-2-amine


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 
    0.263 (Depositor), 0.257 (DCC) 
  • R-Value Work: 
    0.194 (Depositor), 0.187 (DCC) 
  • R-Value Observed: 
    0.198 (Depositor) 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

A Tetrahydrobiopterin-Displacing Potent Neuronal Nitric Oxide Synthase Inhibitor with an Unprecedented Binding Mode.

Weerawarna, P.M.Li, H.Rathnayake, A.D.Hardy, C.D.Poulos, T.L.Silverman, R.B.

(2025) ACS Med Chem Lett 16: 651-659

  • DOI: https://doi.org/10.1021/acsmedchemlett.5c00062
  • Primary Citation of Related Structures:  
    9C1Y, 9C1Z

  • PubMed Abstract: 

    Nitric oxide synthase (NOS) is a pivotal enzyme that regulates various physiological processes, and the dysregulation of neuronal NOS (nNOS) is implicated in neurodegenerative diseases. In our efforts to leverage existing X-ray crystallography data to develop novel aminoquinoline-pyridine hybrid inhibitors and evaluate their inhibitory activities and interactions with NOS isoforms, we identified compounds 8 and 9 as potent human nNOS inhibitors ( K i = 38 and 22 nM, respectively). Notably, compound 8 displayed an unprecedented binding mode, displacing the essential cofactor tetrahydrobiopterin (H 4 B). Furthermore, compound 9 exhibited excellent selectivity, with a 900-fold preference for human nNOS over human eNOS, making it one of the most potent and selective aminoquinoline-based nNOS inhibitors reported to date. Herein we present our inhibitor design rationale, the synthesis, and the biochemical/physical evaluation of binding along with X-ray crystallographic studies with three NOS isoforms, providing detailed insights into the observed potency and selectivity of these inhibitors.


  • Organizational Affiliation

    Departments of Chemistry and Molecular Biosciences, Chemistry of Life Processes Institute, and Center for Developmental Therapeutics, Northwestern University, Evanston, Illinois 60208, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Nitric oxide synthase, brain
A, B, C, D
423Homo sapiensMutation(s): 2 
Gene Names: NOS1
EC: 1.14.13.39
UniProt & NIH Common Fund Data Resources
Find proteins for P29475 (Homo sapiens)
Explore P29475 
Go to UniProtKB:  P29475
PHAROS:  P29475
GTEx:  ENSG00000089250 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP29475
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HEM
Query on HEM

Download Ideal Coordinates CCD File 
E [auth A],
J [auth B],
M [auth C],
R [auth D]
PROTOPORPHYRIN IX CONTAINING FE
C34 H32 Fe N4 O4
KABFMIBPWCXCRK-RGGAHWMASA-L
V5D (Subject of Investigation/LOI)
Query on V5D

Download Ideal Coordinates CCD File 
F [auth A],
K [auth B],
N [auth C],
S [auth D]
7-{[3-({[4-(6-aminopyridin-2-yl)butyl]amino}methyl)phenoxy]methyl}quinolin-2-amine
C26 H29 N5 O
QYKBESYQSCLLGR-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
G [auth A]
H [auth A]
L [auth B]
O [auth C]
P [auth C]
G [auth A],
H [auth A],
L [auth B],
O [auth C],
P [auth C],
T [auth D]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
I [auth B],
Q [auth C]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free:  0.263 (Depositor), 0.257 (DCC) 
  • R-Value Work:  0.194 (Depositor), 0.187 (DCC) 
  • R-Value Observed: 0.198 (Depositor) 
Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 51.973α = 90
b = 164.131β = 90
c = 118.63γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
Aimlessdata scaling
XDSdata reduction
REFMACphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesGM57353

Revision History  (Full details and data files)

  • Version 1.0: 2025-06-11
    Type: Initial release
  • Version 1.1: 2025-08-06
    Changes: Database references