Dynamical characterization of the heme NO oxygen binding (HNOX) domain. Insight into soluble guanylate cyclase allosteric transition.

Full Abstract

Since the discovery of soluble guanylate cyclase (sGC) as the mammalian receptor for nitric oxide (NO), numerous studies have been performed in order to understand how sGC transduces the NO signal. However, the structural basis of sGC activation is still not completely elucidated. Spectroscopic and kinetic studies showed that the key step in the activation mechanism was the NO-induced breaking of the iron proximal histidine bond in the so-called 6c-NO to 5c-NO transition. The main breakthrough in the understanding of sGC activation mechanism came, however, from the elucidation of crystal structures for two different prokaryotic heme NO oxygen (HNOX) domains, which are homologues to the sGC heme domain. In this work we present computer simulation results of Thermoanaerobacter tencogensis HNOX that complement these structural studies, yielding molecular explanations to several poorly understood properties of these proteins. Specifically, our results explain the differential ligand binding patterns of the HNOX domains according to the nature of proximal and distal residues. We also show that the natural dynamics of these proteins is intimately related with the proposed conformational dependent activation process, which involves mainly the alphaFbeta1 loop and the alphaA-alphaC distal subdomain. The results from the sGC models also support this view and suggest a key role for the alphaFbeta1 loop in the iron proximal histidine bond breaking process and, therefore, in the sGC activation mechanism.

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Author information

Author/s: Capece, Luciana (L); Estrin, Dario A (DA); Marti, Marcelo A (MA);

Affiliation: Departamento de Quimica Inorganica, Analitica y Quimica Fisica/INQUIMAE-CONICET, Universidad de Buenos Aires, Ciudad Universitaria, Pabellon 2, Buenos Aires, C1428EHA, Argentina.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Biochemistry (Biochemistry), published in United States. (Language: eng)

Reference: 2008-Sep; vol 47 (issue 36) : pp 9416-27

Dates: Created 2008/09/04; Completed 2008/09/25;

PMID: 18702531, status: MEDLINE (last retrieval date: 11/6/2008)

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Allosteric Regulation - physiology
Animals
Bacterial Proteins - chemistry; genetics; metabolism
Computer Simulation
Enzyme Activation - physiology
Guanylate Cyclase
Heme - chemistry; metabolism
Histidine - chemistry; genetics; metabolism
Humans
Iron - chemistry; metabolism

Iron - chemistry; metabolism
Models, Molecular
Nitric Oxide - chemistry; metabolism
Oxygen - chemistry; metabolism
Protein Binding - physiology
Protein Structure, Secondary - physiology
Protein Structure, Tertiary - physiology
Signal Transduction
Structure-Activity Relationship
Thermoanaerobacter - enzymology; genetics

Associated Chemicals: Bacterial Proteins (0) ; Nitric Oxide (10102-43-9) ; Heme (14875-96-8) ; Histidine (71-00-1) ; Iron (7439-89-6) ; Oxygen (7782-44-7) ; Guanylate Cyclase (EC 4.6.1.2)

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