PDBsum entry 1d1v

Oxidoreductase

PDB id: 1d1v

Contents

Protein chains

416 a.a. *

Ligands

ACT ×4

HEM ×2

H4B ×2

PTU ×2

CAD ×2

GOL ×2

Metals

_ZN

Waters ×627

* Residue conservation analysis

PDB id:

1d1v

Name:

Oxidoreductase

Title:

Bovine endothelial nitric oxide synthase heme domain complexed with s- ethyl-n-phenyl-isothiourea (h4b bound)

Structure:

Bovine endothelial nitric oxide synthase heme. Chain: a, b. Engineered: yes

Source:

Bos taurus. Cattle. Organism_taxid: 9913. Cell: endothelial cells. Expressed in: escherichia coli. Expression_system_taxid: 562

Biol. unit:

Dimer (from PQS)

Resolution:

1.93Å R-factor: 0.186 R-free: 0.219

Authors:

C.S.Raman,H.Li,P.Martasek,G.J.Southan,B.S.S.Masters,T.L.Poulos

Key ref:

C.S.Raman et al. (2001). Implications for isoform-selective inhibitor design derived from the binding mode of bulky isothioureas to the heme domain of endothelial nitric-oxide synthase. J Biol Chem, 276, 26486-26491. PubMed id: 11331290 DOI: 10.1074/jbc.M102255200

Date:

21-Sep-99 Release date: 25-Jul-01

Protein chains

P29473  (NOS3_BOVIN) -  Nitric oxide synthase 3 from Bos taurus

Seq: 1205 a.a.

Struc: 416 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.1.14.13.39 - nitric-oxide synthase (NADPH).
• Reaction: 2 L-arginine + 3 NADPH + 4 O2 + H⁺ = 2 L-citrulline + 2 nitric oxide + 3 NADP⁺ + 4 H2O

2 × L-arginine + 3 × NADPH (Bound ligand (Het Group name = PTU) matches with 50.00% similarity) + 4 × O2 + H(+) = 2 × L-citrulline + 2 × nitric oxide + 3 × NADP(+) + 4 × H2O

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1074/jbc.M102255200

J Biol Chem 276:26486-26491 (2001)

PubMed id: 11331290

Implications for isoform-selective inhibitor design derived from the binding mode of bulky isothioureas to the heme domain of endothelial nitric-oxide synthase.

C.S.Raman, H.Li, P.Martásek, B.R.Babu, O.W.Griffith, B.S.Masters, T.L.Poulos.

ABSTRACT

Nitric oxide produced by nitric-oxide synthase (NOS) is not only involved in a wide range of physiological functions but also in a variety of pathological conditions. Isoform-selective NOS inhibitors are highly desirable to regulate the NO production of one isoform beneficial to normal physiological functions from the uncontrolled NO production of another isoform that accompanies certain pathological states. Crystal structures of the heme domain of the three NOS isoforms have revealed a very high degree of similarity in the immediate vicinity of the heme active site illustrating the challenge of isoform-selective inhibitor design. Isothioureas are potent NOS inhibitors, and the structures of the endothelial NOS heme domain complexed with isothioureas bearing small S-alkyl substituents have been determined (Li, H., Raman, C.S., Martásek, P., Král, V., Masters, B.S.S., and Poulos, T.L. (2000) J. Inorg. Biochem. 81, 133--139). In the present communication, the binding mode of larger bisisothioureas complexed to the endothelial NOS heme domain has been determined. These structures afford a structural rationale for the known inhibitory activities. In addition, these structures provide clues on how to exploit the longer inhibitor substituents that extend out of the active site pocket for isoform-selective inhibitor design.

Selected figure(s)

Figure 3.
Fig. 3. The chemical structures and the abbreviations of compounds discussed in the text.

Figure 5.
Fig. 5. The space-filling drawing of eNOS heme domain with long chain bisisothiourea inhibitor 1,14-BITU modeled in the substrate access channel. The surface residues expected to interact with the ureido of the ligand are labeled.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2001, 276, 26486-26491) copyright 2001.

Figures were selected by an automated process.