Membrane binding

The cyclooxygenase active site lies at the end of a long, narrow, hydrophobic tunnel or channel. Three of the u-helices of the membrane-binding domain lie at the entrance to this tunnel. The... 

The two isozymes are both homodimers, composed of approximately 600 amino acids and possess approximately 60% homology. The three-dimensional structures of COX-1 and COX-2 are very similar. Each one consists of three independent units an epidermal growth factor-like domain, a membrane-binding section and an enzymic domain. The catalytic sites and the residues immediately adjacent are identical but for two small but crucial variations that result in an increase in the volume of the COX-2-active site, enabling it to accept inhibitor-molecules larger than those that could be accommodated in the COX-1 molecule. 

SNAPs is an acronym for soluble NSF attachment proteins. They were originally discovered as cofactors for NSF that mediate the membrane binding of NSF in in vitro transport assays. Several isoforms of SNAPs exist in mammalian cells. SNAPs are also highly conserved proteins. Crystallographic studies indicated that the proteins form a very stiff and twisted sheet that is formed by a series of antiparallel and tightly packed helices connected by short loops. 

Cosme J, Johnson EF. Engineering microsomal cytochrome P450 2C5 to be a soluble, monomeric enzyme. Mutations that alter aggregation, phospholipid dependence of catalysis, and membrane binding. /FtoZ Chem 2000 275 2545-53. 

Williams PA, Cosme J, Sridhar V, Johnson EF, McRee DE. Mammalian microsomal cytochrome P450 monooxygenase structural adaptations for membrane binding and functional diversity. Mol Cell 2000 5 121-31. 

Recent evidence indicates that the 5-HT transporter is subject to post-translational regulatory changes in much the same way as neurotransmitter receptors (Blakeley et al. 1998). Protein kinase A and protein kinase C (PKC), at least, are known to be involved in this process. Phosphorylation of the transporter by PKC reduces the Fmax for 5-HT uptake and leads to sequestration of the transporter into the cell, suggesting that this enzyme has a key role in its intracellular trafficking. Since this phosphorylation is reduced when substrates that are themselves transported across the membrane bind to the transporter (e.g. 5-HT and fi -amphetamine), it seems that the transport of 5-HT is itself linked with the phosphorylation process. Possibly, this process serves as a homeostatic mechanism which ensures that the supply of functional transporters matches the demand for transmitter uptake. By contrast, ligands that are not transported (e.g. cocaine and the selective serotonin reuptake inhibitors (SSRIs)) prevent the inhibition of phosphorylation by transported ligands. Thus, such inhibitors would reduce 5-HT uptake both by their direct inhibition of the transporter and by disinhibition of its phosphorylation (Ramamoorthy and Blakely 1999). 

Bonk, M. et al., Chloroplast import of four carotenoid biosynthetic enzymes in vitro reveals differential fates prior to membrane binding and oligomeric assembly, Eur. J. Biochem. 247, 942, 1997. 

Eischer, H. Passive diffusion and active transport through biological membranes - binding of drugs to... 

Drug instability as delivered from conventional formulation Solubility Biopharmaceutical Low absorption High membrane binding Biological instability Pharmacokinetic and pharmacodynamic Short half-life... 

Membrane Pnxeate/ Membrane Binding Helical Binding... 

Displacement of [3H]DAMGO (p-selective) and [3H]DSLET (6-selective) from rat brain membrane binding sites. 

Bauerle, H.-D. Seelig, J., Interaction of charged and uncharged calcium channel antagonists with phospholipid membranes. Binding equilibrium, binding enthalpy, and membrane location, Biochemistry 30, 7203-7211 (1991). 

Salminen, O., Whiteaker, P., Grady, S.R., Collins, A.C., McIntosh, J.M., Marks, M.J. The subunit composition and pharmacology of alpha-Conotoxin Mil-binding nicotinic acetylcholine receptors studied by a novel membrane-binding assay. Neuropharmacology. 48 696, 2005. 

Perry, D., Davila-Garcia, M., Stockmeier, C., Kellar, K. Increased nicotinic receptors in brains from smokers Membrane binding and autoradiography studies. J. Pharmacol. Exp. Ther. 289 1545, 1999. 

Fluhler E, Burnham VG, Loew LM (1985) Spectra, membrane-binding, and potentiometric responses of new charge shift probes. Biochemistry 24(21) 5749-5755... 

However, when up to 74% phospholipid fractions are used, severe experimental problems arise. With lipophilic sample molecules, the use of concentrated phospholipid artificial membranes leads to two unwanted effects (1) near-complete membrane retention (90-100%) and (2) highly diminished permeability (extinguished in some cases). Both of these effects are presumably due to excessive drug-membrane binding. 

Annexins Phospholipid- and membrane-binding proteins involved in the regulation of cell growth, coagulation, mediation of secretion, signal transduction, and ion channel activity link signaling to membrane dynamics... 

Calpactins calectrin Calpain Calsequestrin Membrane-binding proteins (365) Protease controlling cell adhesion (366) Sequesters calcium within the sarcoplasmic reticulum when muscles relax (80,367)... 

Lambeau, G., Barhanin, J., Schweitz, H., Qar, J. and Lazdunski, M. Identification and properties of very high affinity brain membrane-binding sites for a neurotoxic phosphohpase from the taipan venom. /. Biol. Chem. 264,11503-11510,1989. 

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