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Hydrophilic Residues (hydrophilic + residue)
Selected AbstractsThe solution structure of gomesin, an antimicrobial cysteine-rich peptide from the spiderFEBS JOURNAL, Issue 4 2002Nicolas Mandard Gomesin is the first peptide isolated from spider exhibiting antimicrobial activities. This highly cationic peptide is composed of 18 amino-acid residues including four cysteines forming two disulfide linkages. The solution structure of gomesin has been determined using proton two-dimensional NMR (2D-NMR) and restrained molecular dynamics calculations. The global fold of gomesin consists in a well-resolved two-stranded antiparallel ,,sheet connected by a noncanonical ,,turn. A comparison between the structures of gomesin and protegrin-1 from porcine and androctonin from scorpion outlines several common features in the distribution of hydrophobic and hydrophilic residues. The N- and C-termini, the ,,turn and one face of the ,,sheet are hydrophilic, but the hydrophobicity of the other face depends on the peptide. The similarities suggest that the molecules interact with membranes in an analogous manner. The importance of the intramolecular disulfide bridges in the biological activity of gomesin is being investigated. [source] Calculation of relative binding affinities of fructose 1,6-bisphosphatase mutants with adenosine monophosphate using free energy perturbation methodJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 5 2007Ravichandra Mutyala Abstract The free energy perturbation (FEP) methodology is the most accurate means of estimating relative binding affinities between inhibitors and protein variants. In this article, the importance of hydrophobic and hydrophilic residues to the binding of adenosine monophosphate (AMP) to the fructose 1,6-bisphosphatase (FBPase), a target enzyme for type-II diabetes, was examined by FEP method. Five mutations were made to the FBPase enzyme with AMP inhibitor bound: 113Tyr , 113Phe, 31Thr , 31Ala, 31Thr , 31Ser, 177Met , 177Ala, and 30Leu , 30Phe. These mutations test the strength of hydrogen bonds and van der Waals interactions between the ligand and enzyme. The calculated relative free energies indicated that: 113Tyr and 31Thr play an important role, each via two hydrogen bonds affecting the binding affinity of inhibitor AMP to FBPase, and any changes in these hydrogen bonds due to mutations on the protein will have significant effect on the binding affinity of AMP to FBPase, consistent to experimental results. Also, the free energy calculations clearly show that the hydrophilic interactions are more important than the hydrophobic interactions of the binding pocket of FBPase. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2007 [source] Orexin-A is composed of a highly conserved C -terminal and a specific, hydrophilic N -terminal region, revealing the structural basis of specific recognition by the orexin-1 receptorJOURNAL OF PEPTIDE SCIENCE, Issue 7 2006Tomoyo Takai Abstract Orexins-A and B, also called hypocretins-1 and 2, respectively, are neuropeptides that regulate feeding and sleep-wakefulness by binding to two orphan G protein-coupled receptors named orexin-1 (OX1R) and orexin-2 (OX2R). The sequences and functions of orexins-A and B are similar to each other, but the high sequence homology (68%) is limited in their C -terminal half regions (residues 15,33). The sequence of the N -terminal half region of orexin-A (residues 1,14), containing two disulfide bonds, is very different from that of orexin-B. The structure of orexin-A was determined using two-dimensional homonuclear and 15N and 13C natural abundance heteronuclear NMR experiments. Orexin-A had a compact conformation in the N -terminal half region, which contained a short helix (III:Cys6-Gln9) and was fixed by the two disulfide bonds, and a helix-turn-helix conformation (I:Leu16-Ala23 and II:Asn25-Thr32) in the remaining C -terminal half region. The C -terminal half region had both hydrophobic and hydrophilic residues, which existed on separate surfaces to provide an amphipathic character in helices I and II. The nine residues on the hydrophobic surface are also well conserved in orexin-B, and it was reported that the substitution of each of them with alanine resulted in a significant drop in the functional potency at the receptors. Therefore, we suggest that they form the surface responsible for the main hydrophobic interaction with the receptors. On the other hand, the residues on the hydrophilic surface, together with the hydrophilic residues in the N -terminal half region that form a cluster, are known to make only small contributions to the binding to the receptors through similar alanine-scan experiments. However, since our structure of orexin-A showed that large conformational and electrostatical differences between orexins-A and B were rather concentrated in the N -terminal half regions, we suggest that the region of orexin-A is important for the preference for orexin-A of OX1R. Copyright © 2006 European Peptide Society and John Wiley & Sons, Ltd. [source] Preliminary joint neutron and X-ray crystallographic study of human carbonic anhydrase IIACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 5 2009S. Z. Fisher Carbonic anhydrases catalyze the interconversion of CO2 to HCO3,, with a subsequent proton-transfer (PT) step. PT proceeds via a proposed hydrogen-bonded water network in the active-site cavity that is stabilized by several hydrophilic residues. A joint X-ray and neutron crystallographic study has been initiated to determine the specific water network and the protonation states of the hydrophilic residues that coordinate it in human carbonic anhydrase II. Time-of-flight neutron crystallographic data have been collected from a large (,1.2,mm3) hydrogen/deuterium-exchanged crystal to 2.4,Å resolution and X-ray crystallographic data have been collected from a similar but smaller crystal to 1.5,Å resolution. Obtaining good-quality neutron data will contribute to the understanding of the catalytic mechanisms that utilize water networks for PT in protein environments. [source] A double mutation of Escherichia coli 2C -methyl- d -erythritol-2,4-cyclodiphosphate synthase disrupts six hydrogen bonds with, yet fails to prevent binding of, an isoprenoid diphosphateACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 7 2005Tanja Sgraja The essential enzyme 2C -methyl- d -erythritol-2,4-cyclodiphosphate (MECP) synthase, found in most eubacteria and the apicomplexan parasites, participates in isoprenoid-precursor biosynthesis and is a validated target for the development of broad-spectrum antimicrobial drugs. The structure and mechanism of the enzyme have been elucidated and the recent exciting finding that the enzyme actually binds diphosphate-containing isoprenoids at the interface formed by the three subunits that constitute the active protein suggests the possibility of feedback regulation of MECP synthase. To investigate such a possibility, a form of the enzyme was sought that did not bind these ligands but which would retain the quaternary structure necessary to create the active site. Two amino acids, Arg142 and Glu144, in Escherichia coli MECP synthase were identified as contributing to ligand binding. Glu144 interacts directly with Arg142 and positions the basic residue to form two hydrogen bonds with the terminal phosphate group of the isoprenoid diphosphate ligand. This association occurs at the trimer interface and three of these arginines interact with the ligand phosphate group. A dual mutation was designed (Arg142 to methionine and Glu144 to leucine) to disrupt the electrostatic attractions between the enzyme and the phosphate group to investigate whether an enzyme without isoprenoid diphosphate could be obtained. A low-resolution crystal structure of the mutated MECP synthase Met142/Leu144 revealed that geranyl diphosphate was retained despite the removal of six hydrogen bonds normally formed with the enzyme. This indicates that these two hydrophilic residues on the surface of the enzyme are not major determinants of isoprenoid binding at the trimer interface but rather that hydrophobic interactions between the hydrocarbon tail and the core of the enzyme trimer dominate ligand binding. [source] | ||||||||||