Stereochemistry of polypeptide chain configurations

Ramachandran, G.; Ramakrishnan, C.; Sasisekharan, V.

doi:10.1016/s0022-2836(63)80023-6

Cited by 3,280 publications

(2,199 citation statements)

References 2 publications

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“…Models were generated with the Biopolymer module of SYBYL Ò -X (version 2.0, Tripos International, St. Louis, MO, USA) and energy minimized with restraints using MAE-STRO (version 10.3, Schr€ odinger, New York, NY, USA). This study showed that the cyclic peptide sequence c[ADINNNbA] could be accommodated within the binding site with a backbone root-meansquare deviation (RMSD) of 0.22 A to the crystal structure of the DINNN linear peptide bound to SPSB2 and with no violation of dihedral angles in the Ramachandran plot [24] (Fig. S9).…”

Section: Resultsmentioning

confidence: 99%

Redox‐stable cyclic peptide inhibitors of the SPSB2–iNOS interaction

et al. 2016

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Edited by Barry HalliwellSPSB2 mediates the proteasomal degradation of iNOS. Inhibitors of SPSB2-iNOS interaction are expected to prolong iNOS lifetime and thereby enhance killing of persistent pathogens. Here, we describe the synthesis and characterization of two redox-stable cyclized peptides containing the DINNN motif required for SPSB2 binding. Both analogues bind with low nanomolar affinity to the iNOS binding site on SPSB, as determined by SPR and 19 F NMR, and efficiently displace full-length iNOS from binding to SPSB2 in macrophage cell lysates. These peptides provide a foundation for future development of redox-stable, potent ligands for SPSB proteins as a potential novel class of anti-infectives.Keywords: anti-infective; cyclic peptide; inducible nitric oxide synthase; redox-stable; SPRY domain of the SOCS-box protein 2 SPSB2 protein plays a key role in modulating the lifetime of iNOS in macrophages during infection [1]. It acts as a negative regulator that recruits an E3 ubiquitin ligase complex that polyubiquitinates iNOS and thereby mediates its proteasomal degradation [1]. SPSB2-deficient macrophages exhibit prolonged iNOS expression, NO production and ultimately enhanced killing of persistent pathogens such as Leishmania major parasites and Mycobacterium tuberculosis, suggesting that inhibitors of the SPSB2-iNOS interaction have potential as a new class of anti-infectives [1].Kuang et al. [1] showed that a linear peptide from the disordered N-terminal region of iNOS, KEEK-DINNNVKKT, bound to SPSB2 with a K D of 13 nM, and that the most important residues mediating this interaction were DINNN, in particular the first, third and fifth residues of this sequence motif. In addition, structural studies by X-ray crystallography revealed that the SPRY domain of SPSB2 binds to Asp184, Asn186 and Asn188 of the DINNN sequence of the VASA peptide, the same motif as in the N-terminal region of iNOS (where the corresponding residues are Asp23, Asn25Abbreviations SPSB2, SPRY domain of the SOCS-box protein 2; iNOS, inducible nitric oxide synthase; SPR, surface plasmon

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Section: Resultsmentioning

confidence: 99%

Redox‐stable cyclic peptide inhibitors of the SPSB2–iNOS interaction

et al. 2016

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“…The pivotal role that stereochemistry plays in biasing both residue and motif level conformations in polypeptides was anticipated by, respectively, Ramachandran and Pauling based on modelling considerations. The seminal conclusions reached by these pioneers are strongly affirmed in the database of solved protein structures (Pauling and Corey 1950;Ramachandran et al 1963). A fundamentally important mode of inter-segmental association in Pauling's description of a-helix and b-sheet motifs, is that of hydrogen bonding.…”

Section: Chirality Defining Secondary Structure Of a Polypeptidementioning

confidence: 96%

“…The constraints of planarity and polarity of peptide bonds, and hydrogen bonds between them are responsible for a-helix and b-sheet motifs. Similarly, local sterics, by limiting accessible conformational space, was shown by Ramachandran and Sasisekharan to also favor a-helix and b-sheet regions as the minima on residue level /, w maps (Ramachandran et al 1963;Ramachandran and Sasisekharan 1968). Thus the general principles responsible for secondary structure are well laid out, but the energetic trade off involved in sequence dependent selection of conformation either lacks a consensus about its real physical nature or has not been de-convoluted to all its contributing elements.…”

Section: Introductionmentioning

confidence: 99%

Creating novel protein scripts beyond natural alphabets

Kumar

Ramakrishnan

2010

Syst Synth Biol

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“…Figure 1: The Ramachandran map for chiral L-type amino acids, displaying the permitted rotation angles for the C α bonds in polypeptide chains (Ramachandran 1963). The angles φ and ψ are periodic.…”

Section: Packing Three-dimensional Informationmentioning

confidence: 99%

Carbon — the first frontier of information processing

Patel

2002

J Biosci

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Information is often encoded as an aperiodic chain of building blocks.Modern digital computers use bits as the building blocks, but in general the choice of building blocks depends on the nature of the information to be encoded. What are the optimal building blocks to encode structural information? This can be analysed by substituting the operations of addition and multiplication of conventional arithmetic with translation and rotation.It is argued that at the molecular level, the best component for encoding discretised structural information is carbon. Living organisms discovered this billions of years ago, and used carbon as the back-bone for constructing proteins that function according to their structure. Structural analysis of polypeptide chains shows that an efficient and versatile structural language of 20 building blocks is needed to implement all the tasks carried out by proteins. Properties of amino acids indicate that the present triplet genetic code was preceded by a more primitive one, coding for 10 amino acids using two nucleotide bases.Keywords. Amino acid; aminoacyl-tRNA synthetase; computation; genetic code; information; lattice models; protein structure; quantum search; tetrahedral geometry Structural informationIt is a characteristic of living organisms to acquire information, interpret it and pass it on, often using it and refining it along the way. This information can be in various forms or languages. It can be genetic information passed on from the parent to the offspring, sensory information conveyed by the sense organ to the brain, linguistic information communicated by one being to another, or numerical data entered in a computer for later use. It is advantageous to process the information efficiently, and not in any haphazard manner. In case of living organisms, Darwinian selection during evolution can be considered the driving force for such optimisation. In general, information processing is optimised following two guidelines: minimisation of physical resources (time as well as space), and minimisation of errors.A striking feature of all the forms of information listed above is that the messages are represented as aperiodic chains of discrete building blocks. Such a representation, called digitisation of the message, is commonplace due to its many advantages. Discretisation makes it possible to correct errors arising from local disturbances, and so it is desirable even when the underlying physical variables are continuous (e.g. voltages and currents in computers). It is also easier to handle several variables each spanning a small range than a single variable covering a large range. Any desired message can then be constructed by putting together as many as necessary of the smaller range variables, while the instruction set required to manipulate each variable is substantially simplified. This simplification means that only a limited number of processes have to be physically implemented leading to high speed computation. An important question, therefore, is to figure out the best way...

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Stereochemistry of polypeptide chain configurations

Cited by 3,280 publications

References 2 publications

Redox‐stable cyclic peptide inhibitors of the SPSB2–iNOS interaction

Redox‐stable cyclic peptide inhibitors of the SPSB2–iNOS interaction

Creating novel protein scripts beyond natural alphabets

Carbon — the first frontier of information processing

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