5G0O

Structure of rat neuronal nitric oxide synthase D597N mutant heme domain in complex with 4-METHYL-6-(2-(5-(4-METHYLPIPERAZIN-1-YL) PYRIDIN-3-YL)ETHYL)PYRIDIN-2-AMINE

PDB DOI: https://doi.org/10.2210/pdb5G0O/pdb

Classification: OXIDOREDUCTASE
Organism(s): Rattus norvegicus
Expression System: Escherichia coli BL21(DE3)
Mutation(s): Yes

Deposited: 2016-03-21 Released: 2016-06-15
Deposition Author(s): Li, H., Poulos, T.L.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.85 Å
R-Value Free: 0.233
R-Value Work: 0.193
R-Value Observed: 0.195

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

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

Literature

Electrostatic Control of Isoform Selective Inhibitor Binding in Nitric Oxide Synthase.

Li, H., Wang, H., Kang, S., Silverman, R.B., Poulos, T.L.

(2016) Biochemistry 55: 3702

PubMed: 27250740 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/acs.biochem.6b00261
Primary Citation of Related Structures:
5G0N, 5G0O, 5G0P

PubMed Abstract:
Development of potent and isoform selective nitric oxide synthase (NOS) inhibitors is challenging because of the structural similarity in the heme active sites. One amino acid difference between NOS isoforms, Asp597 in rat neuronal NOS (nNOS) versus Asn368 in bovine endothelial NOS (eNOS), has been identified as the structural basis for why some dipeptide amide inhibitors bind more tightly to nNOS than to eNOS. We now have found that the same amino acid variation is responsible for substantially different binding modes and affinity for a new class of aminopyridine-based inhibitors.

Organizational Affiliation

Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California , Irvine, California 92697-3900, United States.

Macromolecule Content

Total Structure Weight: 100.14 kDa
Atom Count: 7,322
Modelled Residue Count: 819
Deposited Residue Count: 844
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
NITRIC OXIDE SYNTHASE, BRAIN	A, B	422	Rattus norvegicus	Mutation(s): 1 EC: 1.14.13.39
UniProt
Find proteins for P29476 (Rattus norvegicus) Explore P29476 Go to UniProtKB: P29476
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P29476
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 5 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
HEM Query on HEM Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain H [auth B] MOL2 format, chain C [auth A] MOL2 format, chain H [auth B] mmCIF format, chain C [auth A] mmCIF format, chain H [auth B]	C [auth A], H [auth B]	PROTOPORPHYRIN IX CONTAINING FE C₃₄ H₃₂ Fe N₄ O₄ KABFMIBPWCXCRK-RGGAHWMASA-L		Interactions Focus chain C [auth A] Focus chain H [auth B] Interactions & Density Focus chain C [auth A] Focus chain H [auth B]
W64 Query on W64 Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain J [auth B] MOL2 format, chain E [auth A] MOL2 format, chain J [auth B] mmCIF format, chain E [auth A] mmCIF format, chain J [auth B]	E [auth A], J [auth B]	4-methyl-6-(2-(5-(4-methylpiperazin-1-yl)pyridin-3-yl)ethyl)pyridin-2-amine C₁₈ H₂₅ N₅ QJETXLUKROHQMG-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain J [auth B] Interactions & Density Focus chain E [auth A] Focus chain J [auth B]
H4B Query on H4B Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain I [auth B] MOL2 format, chain D [auth A] MOL2 format, chain I [auth B] mmCIF format, chain D [auth A] mmCIF format, chain I [auth B]	D [auth A], I [auth B]	5,6,7,8-TETRAHYDROBIOPTERIN C₉ H₁₅ N₅ O₃ FNKQXYHWGSIFBK-RPDRRWSUSA-N		Interactions Focus chain D [auth A] Focus chain I [auth B] Interactions & Density Focus chain D [auth A] Focus chain I [auth B]
ZN Query on ZN Download Ideal Coordinates CCD File SDF format, chain G [auth A] MOL2 format, chain G [auth A] mmCIF format, chain G [auth A]	G [auth A]	ZINC ION Zn PTFCDOFLOPIGGS-UHFFFAOYSA-N		Interactions Focus chain G [auth A] Interactions & Density Focus chain G [auth A]
ACT Query on ACT Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain K [auth B] MOL2 format, chain F [auth A] MOL2 format, chain K [auth B] mmCIF format, chain F [auth A] mmCIF format, chain K [auth B]	F [auth A], K [auth B]	ACETATE ION C₂ H₃ O₂ QTBSBXVTEAMEQO-UHFFFAOYSA-M		Interactions Focus chain F [auth A] Focus chain K [auth B] Interactions & Density Focus chain F [auth A] Focus chain K [auth B]

Binding Affinity Annotations
ID	Source	Binding Affinity
W64	BindingDB: 5G0O	Ki: min: 42.6, max: 748 (nM) from 4 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.85 Å
R-Value Free: 0.233
R-Value Work: 0.193
R-Value Observed: 0.195
Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 51.7	α = 90
b = 110.71	β = 90
c = 164.17	γ = 90

Software Package:

Software Name	Purpose
PHENIX	refinement
MOSFLM	data reduction
Aimless	data scaling
REFMAC	phasing

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2016-06-15

Deposition Author(s):

Li, H.

Poulos, T.L.

Revision History (Full details and data files)

Version 1.0: 2016-06-15
Type: Initial release
Version 1.1: 2016-07-20
Changes: Database references
Version 1.2: 2024-05-08
Changes: Data collection, Database references, Derived calculations, Other