Hydrogen bonding in globular proteins

Baker, Edward N.; Hubbard, Roderick E.

doi:10.1016/0079-6107(84)90007-5

Cited by 1,719 publications

(1,196 citation statements)

References 93 publications

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“…For Asp 127, Glu 128, and Val 131 the average of the pseudo torsion angles formed by the a-carbon, carbonyl carbon, carbonyl oxygen, and water molecule is 22 f 3". All of these values are very close to those normally observed for water molecules bound to the solvent-exposed residues in the center of an amphiphilic a-helix (Blundell et al, 1983;Baker & Hubbard, 1984;Barlow & Thornton, 1988). Because Ala 130 is partially buried it prevents the bound solvent (#216) at this position from having the standard 22" angle.…”

Section: Surface and Solvent Structuresupporting

confidence: 81%

Multiple alanine replacements within α‐helix 126–134 of T4 lysozyme have independent, additive effects on both structure and stability

1992

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In a systematic attempt to identify residues important in the folding and stability of T4 lysozyme, five amino acids within a-helix 126-134 were substituted by alanine, either singly or in selected combinations. Together with three alanines already present in the wild-type structure this provided a set of mutant proteins with up to eight alanines in sequence. All the variants behaved normally, suggesting that the majority of residues in the a-helix are nonessential for the folding of T4 lysozyme. Of the five individual alanine substitutions it is inferred that four result in slightly increased protein stability and one, the replacement of a buried leucine with alanine, substantially decreased stability. The results support the idea that alanine is a residue of high helix propensity. The change in protein stability observed for each of the multiple mutants is approximately equal to the sum of the energies associated with each of the constituent substitutions.All of the variants could be crystallized isomorphously with wild-type lysozyme, and, with one trivial exception, their structures were determined at high resolution. Substitution of the largely solvent-exposed residues Asp 127, Glu 128, and Val 131 with alanine caused essentially no change in structure except at the immediate site of replacement. Substitutions of the partially buried Asn 132 and the buried Leu 133 with alanine were associated with modest ( 5 0 . 4 A) structural adjustments. The structural changes seen in the multiple mutants were essentially a combination of those seen in the constituent single replacements. The different replacements therefore act essentially independently not only so far as changes in energy are concerned but also in their effect on structure. The destabilizing replacement Leu 133 +Ala made a-helix 126-134 somewhat less regular. Incorporation of additional alanine replacements tended to make the helix more uniform. For the penta-alanine variant a distinct change occurred in a crystal-packing contact, and the "hinge-bending angle" between the amino-and carboxyterminal domains changed by 3.6". This tends to confirm that such hinge-bending in T4 lysozyme is a low-energy conformational change.Keywords: alanine; lysozyme; protein folding; protein structure; thermostability In a systematic attempt to identify residues important in the folding and stability of phage T4 lysozyme we previously substituted four alanines within the a-helix that includes residues 126-134 . The helix is amphipathic, located on the surface of the carboxy-terminal domain, and is remote from the active site ( Fig. 1; Kinemage 1). In wild-type lysozyme this a-helix already includes three alanines. It was found that substitution of three solvent-exposed residues, Glu 128, Val 131, and Asn

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Section: Surface and Solvent Structuresupporting

confidence: 81%

Multiple alanine replacements within α‐helix 126–134 of T4 lysozyme have independent, additive effects on both structure and stability

1992

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“…It is logical to assume that NO interactions are a measure of hydrogen bonding between atoms, but the exact meaning of the CC term is unclear. In a correct structure, the fraction of hydrogen bonded atoms is optimized (Baker & Hubbard, 1984;Stickle et al, 1992), and in an incorrect structure one would expect the fraction of hydrogen bonded atoms to be lower.…”

Section: Resultsmentioning

confidence: 99%

Verification of protein structures: Patterns of nonbonded atomic interactions

1993

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A novel method for differentiating between correctly and incorrectly determined regions of protein structures based on characteristic atomic interactions is described. Different types of atoms are distributed nonrandomly with respect to each other in proteins. Errors in model building lead to more randomized distributions of the different atom types, which can be distinguished from correct distributions by statistical methods.Atoms are classified in one of three categories: carbon (C), nitrogen (N), and oxygen (0). This leads to six different combinations of pairwise noncovalently bonded interactions (CC, CN, CO, NN, NO, and 00). A quadratic error function is used to characterize the set of pairwise interactions from nine-residue sliding windows in a database of 96 reliable protein structures. Regions of candidate protein structures that are mistraced or misregistered can then be identified by analysis of the pattern of nonbonded interactions from each window.

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“…Either way, this can facilitate a hydrogen bond between the charged nitrogen atom and hSERT. 22 The existence of a hydrogen bond in the docking poses is judged from the calculated average distances between the charged nitrogen atom in PP and one of the carboxylate oxygen atoms of Asp98, as well as the backbone carbonyl oxygen atom of Phe335, which are both shorter than 3.5 Å.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Binding of the Amphetamine-like 1-Phenyl-piperazine to Monoamine Transporters

Severinsen

Kraft

Koldsø

et al. 2012

ACS Chem. Neurosci.

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ABSTRACT:The human serotonin transporter (hSERT), the human dopamine transporter (hDAT), and the human norepinephrine transporter (hNET) facilitate the active uptake of the neurotransmitters serotonin, dopamine, and norepinephrine from the synaptic cleft. Drugs of abuse such as MDMA (streetname "ecstasy") and certain 1-phenyl-piperazine (PP) analogs such as 1-(3-chlorophenyl)-piperazine (mCPP) elicit their stimulatory effect by elevating the synaptic concentration of serotonin by blocking or reversing the normal transport activity of hSERT. Recent data suggest that certain analogs of PP may be able to counteract the addictive effect of cocaine. Little is still known about the precise mechanism by which MDMA and PP analogs function at hSERT, hDAT, and hNET and even less is known about the specific protein−ligand interactions. In this study, we provide a comprehensive biochemical examination of a repertoire of PP analogs in hSERT, hDAT, and hNET. Combined with induced fit docking models and molecular dynamics simulations of PP and 1-(3-hydroxyphenyl)-piperazine (3-OH-PP) bound to hSERT and hDAT, we present detailed molecular insight into the promiscuous binding of PP analogs in the monoamine transporters. We find that PP analogs inhibit uptake as well as induce release in all three monoamine transporters. We also find that the selectivity of the PP analogs can be adjusted by carefully selecting substituents on the PP skeleton.

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Hydrogen bonding in globular proteins

Cited by 1,719 publications

References 93 publications

Multiple alanine replacements within α‐helix 126–134 of T4 lysozyme have independent, additive effects on both structure and stability

Multiple alanine replacements within α‐helix 126–134 of T4 lysozyme have independent, additive effects on both structure and stability

Verification of protein structures: Patterns of nonbonded atomic interactions

Binding of the Amphetamine-like 1-Phenyl-piperazine to Monoamine Transporters

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