Conformation of Polypeptides and Proteins

Ramachandran, G.; Sasisekharan, V.

doi:10.1016/s0065-3233(08)60402-7

Cited by 2,941 publications

(1,801 citation statements)

References 166 publications

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“…Totals of 82, 282, and 99 water molecules were built for C:BD1, C:BD2, and C:BD8, respectively, on the basis of a positive 3σ F density in the F o -F c maps. Only residue 326 of C:BD8 was in the disallowed region of the Ramachandran plot as determined by PROCHECK (21,22). Figures were made with Insight II (Accelrys Inc., San Diego) or Molscript (23).…”

Section: Methodsmentioning

confidence: 99%

Balanol Analogues Probe Specificity Determinants and the Conformational Malleability of the Cyclic 3‘,5‘-Adenosine Monophosphate-Dependent Protein Kinase Catalytic Subunit^,

et al. 2003

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The protein kinase family is a prime target for therapeutic agents, since unregulated protein kinase activities are linked to myriad diseases. Balanol, a fungal metabolite consisting of four rings, potently inhibits Ser/Thr protein kinases and can be modified to yield potent inhibitors that are selectives characteristics of a desirable pharmaceutical compound. Here, we characterize three balanol analogues that inhibit cyclic 3′,5′-adenosine monophosphate-dependent protein kinase (PKA) more specifically and potently than calcium-and phospholipid-dependent protein kinase (PKC). Correlation of thermostability and inhibition potency suggests that better inhibitors confer enhanced protection against thermal denaturation. Crystal structures of the PKA catalytic (C) subunit complexed to each analogue show the Gly-rich loop stabilized in an "intermediate" conformation, disengaged from important phosphoryl transfer residues. An analogue that perturbs the PKA C-terminal tail has slightly weaker inhibition potency. The malleability of the PKA C subunit is illustrated by active site residues that adopt alternate rotamers depending on the ligand bound. On the basis of sequence homology to PKA, a preliminary model of the PKC active site is described. The balanol analogues serve to test the model and to highlight differences in the active site local environment of PKA and PKC. The PKA C subunit appears to tolerate balanol analogues with D-ring modifications; PKC does not. We attribute this difference in preference to the variable B helix and C-terminal tail. By understanding the details of ligand binding, more specific and potent inhibitors may be designed that differentiate among closely related AGC protein kinase family members.As cellular processes are better understood at the molecular level, especially in the context of recent genomic information, there has been an increased effort to target specific proteins that are linked to disease. Protein kinases are a diverse family of enzymes that have various regulatory roles yet function similarly by catalyzing the phosphoryl transfer of the γ-phosphate of ATP 1 to an enzyme-specific protein substrate. Since many diseases, including cancer, autoimmune disorders, cardiac disease, and diabetes, are associated with defects in protein phosphorylation, and there are an estimated ∼500 protein kinases in the human genome (1), this family is a major target in the design of pharmaceutical agents and inhibitors. A major challenge for the development of therapeutics is the identification of compounds that have high selectivity. To better understand binding diversity and how this correlates with specificity for protein kinases, three analogues of balanol were studied that specifically inhibit † Portions of this research were carried out at the Stanford Synchrotron Radiation Laboratory, a national user facility operated by Stanford University on behalf of the Office of Basic Energy Sciences, U.S.

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Section: Methodsmentioning

confidence: 99%

Balanol Analogues Probe Specificity Determinants and the Conformational Malleability of the Cyclic 3‘,5‘-Adenosine Monophosphate-Dependent Protein Kinase Catalytic Subunit^,

et al. 2003

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“…O f these, the Ramachandran analysis of peptide dihedral angles (Ramachandran & Sasisekharan, 1968) was one of the first to classify allowed and nonallowed conformations; most grossly misfolded structures can be identified in this fashion. Several other methods that physiochemicallycharacterize a protein structure have been described, including the energetics methods of Novotny et al (1984), the atomic solvation parameter of Eisenberg and McLachlan (1986), and the evaluation of surface polarity (Baumann et al, 1989).…”

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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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“…However, short Ala-based peptides have been suggested to exist in a 310-helix rather than an a-helix (Miick et al, 1992), so both conformations for F4-6 may be possible. The a-helix is also favored energetically over its other variant counterparts (2.2,-, a-, and w-helices) in both right-and left-handed conformations (Ramachandran & Sasisekharan, 1968). Another possible conformation may be an extended left-handed helix as proposed for charged polypeptides and poly-L-Pro (Tiffany & Krimm, 1972; for review see Woody, 1992), but the CD spectra of these peptides display minima in the 197-208-nm range, which is clearly distinct from the 188-190-nm minima seen for some of the F4 peptides.…”

Section: Discussionmentioning

confidence: 99%

Structure of synthetic peptide analogues of an eggshell protein of Schistosoma mansoni

et al. 1993

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The peptide (Gly-L-Tyr-L-Asp-L-Lys-L-Tyr),, referred to as F4-6, was synthesized as a model for a schistosome eggshell protein in which the Gly-Tyr-Asp-Lys-Tyr consensus sequence is repeated over 40 times. Analysis by CD, Fourier transform infrared spectroscopy, potentiometric and spectrophotometric titrations, NMR, and molecular modeling suggests that F4-6 forms some type of left-handed structure. A likely possibility appears to be a lefthanded a-helix stabilized by Lysj-Aspj+, salt bridges and possibly Aspj-Tyrj+, hydrogen bonding and Tyr-Tyr interactions. Spectroscopic studies of a number of F4-6 analogues support this conclusion. For example, substitution of D-Ala for Gly produces a peptide with enhanced left-handed helical spectral characteristics, whereas an L-Ala substitution results in a peptide with minimal structure. These studies suggest that the F4 protein from Schistosoma mansoni may be the first example of a naturally occurring protein devoid of proline and carbohydrate that forms a left-handed helix composed of L-amino acids, although alternative forms of other left-handed structures have yet to be rigorously excluded.Keywords: F4-6 peptide; Schistosoma mansoni; schistosome eggshell protein The pathology of schistosomiasis is due to the inflammatory response to the eggs of the parasitic trematode, Schistosoma mansoni (or other closely related schistosomes) lodged in the hosts' body tissues. Granulomas form around the eggs in response to soluble carbohydrate and protein antigens secreted by the eggs. When an egg is deposited by the female schistosome, it contains a fertilized ovum and 30-40 vitelline cells. Development of the miracidium larva occurs inside the eggshell lodged in the host tissues. The eggshell is formed shortly before egg laying from protein precursors secreted by the vitelline cells that subsequently become surrounded by the eggshell. These vitelline cells serve as a food supply for the developing miracidium and disappear before hatching. The secreted

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Conformation of Polypeptides and Proteins

Cited by 2,941 publications

References 166 publications

Balanol Analogues Probe Specificity Determinants and the Conformational Malleability of the Cyclic 3‘,5‘-Adenosine Monophosphate-Dependent Protein Kinase Catalytic Subunit^,

Balanol Analogues Probe Specificity Determinants and the Conformational Malleability of the Cyclic 3‘,5‘-Adenosine Monophosphate-Dependent Protein Kinase Catalytic Subunit^,

Verification of protein structures: Patterns of nonbonded atomic interactions

Structure of synthetic peptide analogues of an eggshell protein of Schistosoma mansoni

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Conformation of Polypeptides and Proteins

Cited by 2,941 publications

References 166 publications

Balanol Analogues Probe Specificity Determinants and the Conformational Malleability of the Cyclic 3‘,5‘-Adenosine Monophosphate-Dependent Protein Kinase Catalytic Subunit,

Balanol Analogues Probe Specificity Determinants and the Conformational Malleability of the Cyclic 3‘,5‘-Adenosine Monophosphate-Dependent Protein Kinase Catalytic Subunit,

Verification of protein structures: Patterns of nonbonded atomic interactions

Structure of synthetic peptide analogues of an eggshell protein of Schistosoma mansoni

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Balanol Analogues Probe Specificity Determinants and the Conformational Malleability of the Cyclic 3‘,5‘-Adenosine Monophosphate-Dependent Protein Kinase Catalytic Subunit^,

Balanol Analogues Probe Specificity Determinants and the Conformational Malleability of the Cyclic 3‘,5‘-Adenosine Monophosphate-Dependent Protein Kinase Catalytic Subunit^,