scholarly journals Ligand-Binding-Site Structure Refinement Using Molecular Dynamics with Restraints Derived from Predicted Binding Site Templates

2019 ◽  
Vol 15 (11) ◽  
pp. 6524-6535 ◽  
Author(s):  
Hugo Guterres ◽  
Hui Sun Lee ◽  
Wonpil Im
Keyword(s):  
Molecular Dynamics ◽  
Ligand Binding ◽  
Binding Site ◽  
Structure Refinement ◽  
Ligand Binding Site ◽  
Site Structure ◽  
Predicted Binding Site

scholarly journals Ligand-Binding-Site Structure Shapes Allosteric Signal Transduction and the Evolution of Allostery in Protein Complexes

2019 ◽  
Vol 36 (8) ◽  
pp. 1711-1727 ◽  
Author(s):  
György Abrusán ◽  
Joseph A Marsh
Keyword(s):  
Signal Transduction ◽  
Ligand Binding ◽  
Binding Site ◽  
Binding Sites ◽  
Quaternary Structure ◽  
Protein Complexes ◽  
Signal Transduction Pathways ◽  
Ligand Binding Site ◽  
Single Chain ◽  
Site Structure

Abstract The structure of ligand-binding sites has been shown to profoundly influence the evolution of function in homomeric protein complexes. Complexes with multichain binding sites (MBSs) have more conserved quaternary structure, more similar binding sites and ligands between homologs, and evolve new functions slower than homomers with single-chain binding sites (SBSs). Here, using in silico analyses of protein dynamics, we investigate whether ligand-binding-site structure shapes allosteric signal transduction pathways, and whether the structural similarity of binding sites influences the evolution of allostery. Our analyses show that: 1) allostery is more frequent among MBS complexes than in SBS complexes, particularly in homomers; 2) in MBS homomers, semirigid communities and critical residues frequently connect interfaces and thus they are characterized by signal transduction pathways that cross protein–protein interfaces, whereas SBS homomers usually not; 3) ligand binding alters community structure differently in MBS and SBS homomers; and 4) except MBS homomers, allosteric proteins are more likely to have homologs with similar binding site than nonallosteric proteins, suggesting that binding site similarity is an important factor driving the evolution of allostery.

Constraints of Opsin Structure on the Ligand-binding Site: Studies with Ring-fused Retinals¶

2002 ◽  
Vol 76 (6) ◽  
pp. 606 ◽  
Author(s):  
Takahiro Hirano ◽  
In Taek Lim ◽  
Don Moon Kim ◽  
Xiang-Guo Zheng ◽  
Kazuo Yoshihara ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Binding Site ◽  
Ligand Binding Site

scholarly journals The Interplay of Cholesterol and Ligand Binding in hTSPO from Classical Molecular Dynamics Simulations

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1250
Author(s):  
Hien T. T. Lai ◽  
Alejandro Giorgetti ◽  
Giulia Rossetti ◽  
Toan T. Nguyen ◽  
Paolo Carloni ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Ligand Binding ◽  
Molecular Dynamics Simulations ◽  
Binding Site ◽  
Transmembrane Protein ◽  
Free Form ◽  
Experimental Investigations ◽  
Terminal Part ◽  
Dynamics Simulations ◽  
Cholesterol Binding

The translocator protein (TSPO) is a 18kDa transmembrane protein, ubiquitously present in human mitochondria. It is overexpressed in tumor cells and at the sites of neuroinflammation, thus representing an important biomarker, as well as a promising drug target. In mammalian TSPO, there are cholesterol–binding motifs, as well as a binding cavity able to accommodate different chemical compounds. Given the lack of structural information for the human protein, we built a model of human (h) TSPO in the apo state and in complex with PK11195, a molecule routinely used in positron emission tomography (PET) for imaging of neuroinflammatory sites. To better understand the interactions of PK11195 and cholesterol with this pharmacologically relevant protein, we ran molecular dynamics simulations of the apo and holo proteins embedded in a model membrane. We found that: (i) PK11195 stabilizes hTSPO structural fold; (ii) PK11195 might enter in the binding site through transmembrane helices I and II of hTSPO; (iii) PK11195 reduces the frequency of cholesterol binding to the lower, N–terminal part of hTSPO in the inner membrane leaflet, while this impact is less pronounced for the upper, C–terminal part in the outer membrane leaflet, where the ligand binding site is located; (iv) very interestingly, cholesterol most frequently binds simultaneously to the so-called CRAC and CARC regions in TM V in the free form (residues L150–X–Y152–X(3)–R156 and R135–X(2)–Y138–X(2)–L141, respectively). However, when the protein is in complex with PK11195, cholesterol binds equally frequently to the CRAC–resembling motif that we observed in TM I (residues L17–X(2)–F20–X(3)–R24) and to CRAC in TM V. We expect that the CRAC–like motif in TM I will be of interest in future experimental investigations. Thus, our MD simulations provide insight into the structural features of hTSPO and the previously unknown interplay between PK11195 and cholesterol interactions with this pharmacologically relevant protein.

Capturing of the free cysteine residue in the ligand-binding site by affinity labeling of the ORL1 nociceptin receptor

2011 ◽  
Vol 19 (24) ◽  
pp. 7597-7602 ◽  
Author(s):  
Ayami Matsushima ◽  
Hirokazu Nishimura ◽  
Shogo Inamine ◽  
Shiho Uemura ◽  
Yasuyuki Shimohigashi
Keyword(s):  
Ligand Binding ◽  
Binding Site ◽  
Cysteine Residue ◽  
Affinity Labeling ◽  
Ligand Binding Site ◽  
Nociceptin Receptor
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