MSDC-0160 and MSDC-0602 Binding with Human Mitochondrial Pyruvate Carrier (MPC) 1 and 2 Heterodimer

2021 ◽  
pp. 427-455
Author(s):  
Clyde F. Phelix ◽  
Allen K. Bourdon ◽  
Jason L Dugan ◽  
Greg Villareal ◽  
George Perry
Keyword(s):  
Diabetes Mellitus ◽  
Data Base ◽  
Homology Model ◽  
Ligand Docking ◽  
Mutant Form ◽  
Therapeutic Drugs ◽  
Multiple Binding Sites ◽  
Mitochondrial Pyruvate Carrier ◽  
Multiple Binding ◽  
Novel Target

The mitochondrial pyruvate carrier (MPC) is a novel target for therapeutic drugs to treat Alzheimer's and Parkinson's disease, diabetes mellitus, and non-alcoholic steatohepatitis (NASH). Metabolic Solutions Development Company (MSDC) has two thiazolidinediones, MSDC-0160 and MSDC-0602, in the pipeline. This report describes results for a MPC1/2 heterodimer homology model. The FASTA sequences for MPC1 and MPC2 were accessed from UniProt and submitted to RaptorX, resulting in best candidate monomeric “protein data base” files for each. One mutant form of MPC1, L36I, was also processed. These were submitted to PyDock to generate best candidate MPC1/2 heterodimer models that were used for ligand docking analyses with AutoDock Vina and “Rosetta Online Server that Includes Everyone” (ROSIE). Multiple binding sites for pyruvate and both drugs were found on both MPC1 and MPC2 subunits with drugs having nearly double the affinity in each case except the intermediate and open-in states for the L36I mutant transporter.

MSDC-0160 and MSDC-0602 Binding with Human Mitochondrial Pyruvate Carrier (MPC) 1 and 2 Heterodimer

2017 ◽  
Vol 7 (2) ◽  
pp. 43-67 ◽  
Author(s):  
Clyde F. Phelix ◽  
Allen K Bourdon ◽  
Jason L Dugan ◽  
Greg Villareal ◽  
George Perry
Keyword(s):  
Binding Sites ◽  
Homology Model ◽  
Ligand Docking ◽  
Mutant Form ◽  
Autodock Vina ◽  
Therapeutic Drugs ◽  
Multiple Binding Sites ◽  
Mitochondrial Pyruvate Carrier ◽  
Multiple Binding ◽  
Novel Target

The mitochondrial pyruvate carrier (MPC) is a novel target for therapeutic drugs to treat Alzheimer's and Parkinson's disease, diabetes mellitus, and non-alcoholic steatohepatitis (NASH). Metabolic Solutions Development Company (MSDC) has two thiazolidinediones, MSDC-0160 and MSDC-0602, in the pipeline. This report describes results for a MPC1/2 heterodimer homology model. The FASTA sequences for MPC1 and MPC2 were accessed from UniProt and submitted to RaptorX, resulting in best candidate monomeric “protein data base” files for each. One mutant form of MPC1, L36I, was also processed. These were submitted to PyDock to generate best candidate MPC1/2 heterodimer models that were used for ligand docking analyses with AutoDock Vina and “Rosetta Online Server that Includes Everyone” (ROSIE). Multiple binding sites for pyruvate and both drugs were found on both MPC1 and MPC2 subunits with drugs having nearly double the affinity in each case except the intermediate and open-in states for the L36I mutant transporter.

NMDAR PAMs: Multiple Chemotypes for Multiple Binding Sites

2019 ◽  
Vol 19 (24) ◽  
pp. 2239-2253 ◽  
Author(s):  
Paul J. Goldsmith
Keyword(s):  
Binding Sites ◽  
Receptor Activation ◽  
Research Area ◽  
Allosteric Modulators ◽  
Nonselective Cation Channels ◽  
Multiple Binding Sites ◽  
Multiple Binding ◽  
Excitatory Neurotransmission ◽  
Psychiatric Conditions ◽  
High Level

The N-methyl-D-aspartate receptor (NMDAR) is a member of the ionotropic glutamate receptor (iGluR) family that plays a crucial role in brain signalling and development. NMDARs are nonselective cation channels that are involved with the propagation of excitatory neurotransmission signals with important effects on synaptic plasticity. NMDARs are functionally and structurally complex receptors, they exist as a family of subtypes each with its own unique pharmacological properties. Their implication in a variety of neurological and psychiatric conditions means they have been a focus of research for many decades. Disruption of NMDAR-related signalling is known to adversely affect higherorder cognitive functions (e.g. learning and memory) and the search for molecules that can recover (or even enhance) receptor output is a current strategy for CNS drug discovery. A number of positive allosteric modulators (PAMs) that specifically attempt to overcome NMDAR hypofunction have been discovered. They include various chemotypes that have been found to bind to several different binding sites within the receptor. The heterogeneity of chemotype, binding site and NMDAR subtype provide a broad landscape of ongoing opportunities to uncover new features of NMDAR pharmacology. Research on NMDARs continues to provide novel mechanistic insights into receptor activation and this review will provide a high-level overview of the research area and discuss the various chemical classes of PAMs discovered so far.

Effects of Multiple Binding Sites on Studies of Hydrogen Bonding between Nitroxide Radicals and Solvent Molecules

1993 ◽  
Vol 58 (1) ◽  
pp. 47-52 ◽  
Author(s):  
Imad Al-Bala'a ◽  
Richard D. Bates
Keyword(s):  
Hydrogen Bonding ◽  
Magnetic Resonance ◽  
Binding Site ◽  
Binding Sites ◽  
Hyperfine Coupling Constant ◽  
Hydrogen Donor ◽  
Complex Formation Constants ◽  
Multiple Binding Sites ◽  
Multiple Binding ◽  
Solvent Molecules

The role of more than one binding site on a nitroxide free radical in magnetic resonance determinations of the properties of the complex formed with a hydrogen donor is examined. The expression that relates observed hyperfine couplings in EPR spectra to complex formation constants and concentrations of each species in solution becomes much more complex when multiple binding sites are present, but reduces to a simpler form when binding at the two sites occurs independently and the binding at the non-nitroxide site does not produce significant differences in the hyperfine coupling constant in the complexed radical. Effects on studies of hydrogen bonding between multiple binding site nitroxides and hydrogen donor solvent molecules by other magnetic resonance methods are potentially more extreme.

scholarly journals Cryo-EM structure of human Wntless in complex with Wnt3a

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Qing Zhong ◽  
Yanyu Zhao ◽  
Fangfei Ye ◽  
Zaiyu Xiao ◽  
Gaoxingyu Huang ◽  
...  
Keyword(s):  
Transmembrane Domain ◽  
Transmembrane Protein ◽  
Multiple Interfaces ◽  
Wnt Proteins ◽  
Binding Partners ◽  
Multiple Binding Sites ◽  
Evolutionarily Conserved ◽  
Multiple Binding ◽  
Hydrophobic Tunnel ◽  
Conserved Core

AbstractWntless (WLS), an evolutionarily conserved multi-pass transmembrane protein, is essential for secretion of Wnt proteins. Wnt-triggered signaling pathways control many crucial life events, whereas aberrant Wnt signaling is tightly associated with many human diseases including cancers. Here, we report the cryo-EM structure of human WLS in complex with Wnt3a, the most widely studied Wnt, at 2.2 Å resolution. The transmembrane domain of WLS bears a GPCR fold, with a conserved core cavity and a lateral opening. Wnt3a interacts with WLS at multiple interfaces, with the lipid moiety on Wnt3a traversing a hydrophobic tunnel of WLS transmembrane domain and inserting into membrane. A β-hairpin of Wnt3a containing the conserved palmitoleoylation site interacts with WLS extensively, which is crucial for WLS-mediated Wnt secretion. The flexibility of the Wnt3a loop/hairpin regions involved in the multiple binding sites indicates induced fit might happen when Wnts are bound to different binding partners. Our findings provide important insights into the molecular mechanism of Wnt palmitoleoylation, secretion and signaling.

MPC1 is essential for PGC-1α-induced mitochondrial respiration and biogenesis

2018 ◽  
Vol 475 (10) ◽  
pp. 1687-1699 ◽  
Author(s):  
Eunjin Koh ◽  
Young Kyung Kim ◽  
Daye Shin ◽  
Kyung-Sup Kim
Keyword(s):  
Target Gene ◽  
Peroxisome Proliferator ◽  
Mitochondrial Matrix ◽  
Strong Suppression ◽  
Mitochondrial Oxygen Consumption ◽  
Peroxisome Proliferator Activated Receptor ◽  
Human Renal Cell Carcinoma ◽  
Mitochondrial Pyruvate Carrier ◽  
Novel Target ◽  
Estrogen Related Receptor

Mitochondrial pyruvate carrier (MPC), which is essential for mitochondrial pyruvate usage, mediates the transport of cytosolic pyruvate into mitochondria. Low MPC expression is associated with various cancers, and functionally associated with glycolytic metabolism and stemness. However, the mechanism by which MPC expression is regulated is largely unknown. In this study, we showed that MPC1 is down-regulated in human renal cell carcinoma (RCC) due to strong suppression of peroxisome proliferator-activated receptor-gamma co-activator (PGC)-1 alpha (PGC-1α). We also demonstrated that overexpression of PGC-1α stimulates MPC1 transcription, while depletion of PGC-1α by siRNA suppresses MPC expression. We found that PGC-1α interacts with estrogen-related receptor-alpha (ERR-α) and recruits it to the ERR-α response element motif located in the proximal MPC1 promoter, resulting in efficient activation of MPC1 expression. Furthermore, the MPC inhibitor, UK5099, blocked PGC-1α-induced pyruvate-dependent mitochondrial oxygen consumption. Taken together, our results suggest that MPC1 is a novel target gene of PGC-1α. In addition, low expression of PGC-1α in human RCC might contribute to the reduced expression of MPC, resulting in impaired mitochondrial respiratory capacity in RCC by limiting the transport of pyruvate into the mitochondrial matrix.

scholarly journals Heparan sulfate and heparin interactions with proteins

2015 ◽  
Vol 12 (110) ◽  
pp. 20150589 ◽  
Author(s):  
Maria C. Z. Meneghetti ◽  
Ashley J. Hughes ◽  
Timothy R. Rudd ◽  
Helena B. Nader ◽  
Andrew K. Powell ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Ex Vivo ◽  
Sequence Specificity ◽  
Structure Activity ◽  
Multiple Binding Sites ◽  
Multiple Binding ◽  
Heparin Activity

Heparan sulfate (HS) polysaccharides are ubiquitous components of the cell surface and extracellular matrix of all multicellular animals, whereas heparin is present within mast cells and can be viewed as a more sulfated, tissue-specific, HS variant. HS and heparin regulate biological processes through interactions with a large repertoire of proteins. Owing to these interactions and diverse effects observed during in vitro , ex vivo and in vivo experiments, manifold biological/pharmacological activities have been attributed to them. The properties that have been thought to bestow protein binding and biological activity upon HS and heparin vary from high levels of sequence specificity to a dependence on charge. In contrast to these opposing opinions, we will argue that the evidence supports both a level of redundancy and a degree of selectivity in the structure–activity relationship. The relationship between this apparent redundancy, the multi-dentate nature of heparin and HS polysaccharide chains, their involvement in protein networks and the multiple binding sites on proteins, each possessing different properties, will also be considered. Finally, the role of cations in modulating HS/heparin activity will be reviewed and some of the implications for structure–activity relationships and regulation will be discussed.

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