Ligand Binding to the Fe(III)-Protoporphyrin IX Complex of Phosphodiesterase fromEscherichia coli(EcDOS) Markedly Enhances Catalysis of Cyclic di-GMP: Roles of Met95, Arg97, and Phe113 of the Putative Heme Distal Side in Catalytic Regulation and Ligand Binding†

Biochemistry ◽  
2008 ◽  
Vol 47 (50) ◽  
pp. 13438-13446 ◽  
Author(s):  
Atsunari Tanaka ◽  
Toru Shimizu
Keyword(s):  
Ligand Binding ◽  
Protoporphyrin Ix ◽  
Fromescherichia Coli ◽  
Distal Side

scholarly journals Characterization of the High-Affinity Drug Ligand Binding Site of Mouse Recombinant TSPO

2019 ◽  
Vol 20 (6) ◽  
pp. 1444 ◽  
Author(s):  
Soria Iatmanen-Harbi ◽  
lucile Senicourt ◽  
Vassilios Papadopoulos ◽  
Olivier Lequin ◽  
Jean-Jacques Lacapere
Keyword(s):  
Ligand Binding ◽  
Binding Site ◽  
Conformational Changes ◽  
Protoporphyrin Ix ◽  
Binding Pocket ◽  
Site Directed Mutagenesis ◽  
Translocator Protein ◽  
Binding Affinities ◽  
Ligand Selectivity ◽  
High Affinity

The optimization of translocator protein (TSPO) ligands for Positron Emission Tomography as well as for the modulation of neurosteroids is a critical necessity for the development of TSPO-based diagnostics and therapeutics of neuropsychiatrics and neurodegenerative disorders. Structural hints on the interaction site and ligand binding mechanism are essential for the development of efficient TSPO ligands. Recently published atomic structures of recombinant mammalian and bacterial TSPO1, bound with either the high-affinity drug ligand PK 11195 or protoporphyrin IX, have revealed the membrane protein topology and the ligand binding pocket. The ligand is surrounded by amino acids from the five transmembrane helices as well as the cytosolic loops. However, the precise mechanism of ligand binding remains unknown. Previous biochemical studies had suggested that ligand selectivity and binding was governed by these loops. We performed site-directed mutagenesis to further test this hypothesis and measured the binding affinities. We show that aromatic residues (Y34 and F100) from the cytosolic loops contribute to PK 11195 access to its binding site. Limited proteolytic digestion, circular dichroism and solution two-dimensional (2-D) NMR using selective amino acid labelling provide information on the intramolecular flexibility and conformational changes in the TSPO structure upon PK 11195 binding. We also discuss the differences in the PK 11195 binding affinities and the primary structure between TSPO (TSPO1) and its paralogous gene product TSPO2.

Ligand Binding Dynamics to the Heme Domain of the Oxygen Sensor Dos fromEscherichia coli

Biochemistry ◽  
2003 ◽  
Vol 42 (21) ◽  
pp. 6527-6535 ◽  
Author(s):  
Ursula Liebl ◽  
Latifa Bouzhir-Sima ◽  
Laurent Kiger ◽  
Michael C. Marden ◽  
Jean-Christophe Lambry ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Oxygen Sensor ◽  
Fromescherichia Coli ◽  
Heme Domain

Impact of Distal Side Water and Residue 315 on Ligand Binding to FerricMycobacterium tuberculosisCatalase−Peroxidase (KatG)†

Biochemistry ◽  
2008 ◽  
Vol 47 (47) ◽  
pp. 12583-12592 ◽  
Author(s):  
Kalina Ranguelova ◽  
Javier Suarez ◽  
Leonid Metlitsky ◽  
Shengwei Yu ◽  
Shelly Zev Brejt ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Distal Side

scholarly journals A computational study of ligand binding affinities in iron(iii) porphine and protoporphyrin IX complexes

2014 ◽  
Vol 43 (25) ◽  
pp. 9754-9765 ◽  
Author(s):  
Marcus C. Durrant
Keyword(s):  
Density Functional Theory ◽  
Ligand Binding ◽  
Antimalarial Drug ◽  
Malaria Parasite ◽  
Density Functional ◽  
Computational Study ◽  
Protoporphyrin Ix ◽  
Binding Affinities ◽  
Functional Theory ◽  
Key Events

In the context of antimalarial drug development, density functional theory has been used to model the interactions between a diverse set of 31 small ligands and the iron(iii) centre of ferriprotoporphyrin IX, as well as key events in the crystallization of this molecule by the malaria parasite.

Arg97 at the Heme-Distal Side of the Isolated Heme-Bound PAS Domain of a Heme-Based Oxygen Sensor fromEscherichia coli(EcDOS) Plays Critical Roles in Autoxidation and Binding to Gases, Particularly O2†

Biochemistry ◽  
2008 ◽  
Vol 47 (34) ◽  
pp. 8874-8884 ◽  
Author(s):  
Yukako Ishitsuka ◽  
Yasuyuki Araki ◽  
Atsunari Tanaka ◽  
Jotaro Igarashi ◽  
Osamu Ito ◽  
...  
Keyword(s):  
Oxygen Sensor ◽  
Pas Domain ◽  
Fromescherichia Coli ◽  
Distal Side

scholarly journals Mycobacterial and Human Ferrous Nitrobindins: Spectroscopic and Reactivity Properties

2021 ◽  
Vol 22 (4) ◽  
pp. 1674
Author(s):  
Giovanna De Simone ◽  
Alessandra di Masi ◽  
Alessandra Pesce ◽  
Martino Bolognesi ◽  
Chiara Ciaccio ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Ph Dependence ◽  
Dissociation Rate ◽  
Heme Pocket ◽  
Functional Relationships ◽  
Distal Side ◽  
Structural And Functional Properties ◽  
Marked Enhancement ◽  
Ph Range ◽  
Dissociation Rate Constants

Structural and functional properties of ferrous Mycobacterium tuberculosis (Mt-Nb) and human (Hs-Nb) nitrobindins (Nbs) were investigated. At pH 7.0 and 25.0 °C, the unliganded Fe(II) species is penta-coordinated and unlike most other hemoproteins no pH-dependence of its coordination was detected over the pH range between 2.2 and 7.0. Further, despite a very open distal side of the heme pocket (as also indicated by the vanishingly small geminate recombination of CO for both Nbs), which exposes the heme pocket to the bulk solvent, their reactivity toward ligands, such as CO and NO, is significantly slower than in most hemoproteins, envisaging either a proximal barrier for ligand binding and/or crowding of H2O molecules in the distal side of the heme pocket which impairs ligand binding to the heme Fe-atom. On the other hand, liganded species display already at pH 7.0 and 25 °C a severe weakening (in the case of CO) and a cleavage (in the case of NO) of the proximal Fe-His bond, suggesting that the ligand-linked movement of the Fe(II) atom onto the heme plane brings about a marked lengthening of the proximal Fe-imidazole bond, eventually leading to its rupture. This structural evidence is accompanied by a marked enhancement of both ligands dissociation rate constants. As a whole, these data clearly indicate that structural–functional relationships in Nbs strongly differ from what observed in mammalian and truncated hemoproteins, suggesting that Nbs play a functional role clearly distinct from other eukaryotic and prokaryotic hemoproteins.

scholarly journals Monomeric state and ligand binding of recombinant GABA transporter fromEscherichia coli

FEBS Letters ◽  
2001 ◽  
Vol 494 (3) ◽  
pp. 165-169 ◽  
Author(s):  
Xiao-Dan Li ◽  
Anthony Villa ◽  
Colleen Gownley ◽  
Myong Jin Kim ◽  
Jinmei Song ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Gaba Transporter ◽  
Fromescherichia Coli
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