The crystal structure of papain C

Drenth, Jan; Jansonius, Johan N.; Koekoek, Roelof; Marrink, J; Munnik, J.; Wolthers, B.G.

doi:10.1016/s0022-2836(62)80028-x

Cited by 22 publications

(2 citation statements)

References 9 publications

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“…In this context, three-dimensional structures are a necessity. Accurate X-ray structures are now available for several members of the C1 family: papain (Drenth et al, 1962;Kamphuis et al, 1984;Pickersgill et al, 1992), actinidin (Baker, 1980), caricain (Pickersgill et al, 1991, glycyl endopeptidase (O'Hara et al, 1995), cruzipain (Mc Grath et al, 1995), and rat and human cathepsins B (Jia et al, 1995;Musil et al, 1991).…”

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confidence: 99%

Structure of Chymopapain at 1.7 Å Resolution

et al. 1996

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The X-ray structure of chymopapain, a cysteine proteinase isolated from the latex of the fruits of Carica papaya L., has been determined by molecular replacement methods and refined to a conventional R factor of 0.19 for all observed reflections in the range from 9.5 to 1.7 A resolution. The crystals used in this study contained a unique molecular species of chymopapain with two moles of thiomethyl attached to the two free cysteines per mole of enzyme. A comparison is made with the other known papaya proteinase X-ray structures: papain, caricain, and glycyl endopeptidase. Their backbone conformations are extremely similar except for two loop regions. Both regions are located at the surface of the protein and far away of the active site cleft. In each X-ray structure the same water network was found at the interface between the two domains of the enzyme. A close examination of the active site groove showed that the specificity restrictions dictated by the S2 subsite did not differ significantly among the four proteinases.

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confidence: 99%

Structure of Chymopapain at 1.7 Å Resolution

et al. 1996

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“…As a result of these researches, long sequences of amino acid residues have been established, and there is reason to hope that continuation of this work will lead to a complete elucidation of the primary structure of the enzyme. The tertiary structure is being investigated by Drenth and his collaborators (Drenth & Jansonius, 1959;Drenth et al 1962) by X-ray analysis.…”

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Direct Evidence for an Acylated Thiol as an Intermediate in Papain- And Ficin-Catalysed Hydrolyses

Lowe¹,

Williams²

1965

Biochemical Journal

108

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1. Methyl thionohippurate was prepared and shown to be a specific substrate for both papain and ficin. 2. The ultraviolet-absorption properties of the acyl-enzyme intermediate for both papain and ficin with methyl thionohippurate was that expected of an acyl-thiol. The possibility that other functional groups present in papain or ficin might be the site of acylation has been excluded. 3. The change in extinction at the absorption maximum with time was as expected for the acyl-enzyme on the basis of the known Michaelis-Menten parameters for methyl thionohippurate. 4. The variation of extinction with initial substrate concentration for both papain and ficin was that expected from the Michaelis-Menten parameters. 5. The extinction of the absorption maximum of the thionohippuryl-enzyme intermediate was suppressed by the addition of methyl hippurate to the extent predicted from the Michaelis-Menten parameters. 6. The decay of the extinction for the acyl-enzyme was arrested by adjusting the pH of the solution to 2.5. 7. These experiments provide compelling evidence that the acylation by substrate of both papain and ficin takes place through a thiol residue.

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Peptidomimetics for Drug Design

Estiarte

Rich

2003

Burger's Medicinal Chemistry and Drug Discovery

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The past and present role of peptidomimetics to drug discovery and protein design is summarized. The historical evolution of this area of research and the current state‐of‐the‐art research strategies are described. A detailed description of each of the peptidomimetics types that have appeared in the literature so far is discussed. Some examples are used to illustrate the drug design process that proceeds from the native peptide to a completely non‐peptide peptidomimetic structure. Special attention is given to important pharmaceutical targets such as the cysteine, metallo, serineor aspartic proteases, integrins, G‐protein–coupled receptors, etc. The principles currently used are highlighted in the discussions of some of the most successful examples. It is obvious that major progress in this area is primarily derived of recent advances in all aspects of science. Molecular modeling, X‐ray crystallography, and high field NMR have greatly contributed to this endeavor. Peptidomimetic inhibitors were traditionally developed by modifying peptide bonds, by mimicking the transition states for enzyme‐catalyzed reactions, or by constraining the conformational mobility of a peptide‐derived chain; the latter was used to overcome some of the pharmacokinetic barriers encountered in using peptides as drugs. Lately, these difficulties have been partially solved with rational drug design of de novo compounds. Several methods have been successfully applied, with noteworthy examples currently in clinical trials, and many others are expected in the near future. It would be wrong, however, to imply that this process is a universal panacea. New ideas are urgently needed to produce clinical candidates faster and to solve some of the undesired pharmacokinetic issues.

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The crystal structure of papain C

Cited by 22 publications

References 9 publications

Structure of Chymopapain at 1.7 Å Resolution

Structure of Chymopapain at 1.7 Å Resolution

Direct Evidence for an Acylated Thiol as an Intermediate in Papain- And Ficin-Catalysed Hydrolyses

Peptidomimetics for Drug Design

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