High-resolution structure of a potent, cyclic proteinase inhibitor from sunflower seeds

Luckett, S; Garcia, R.S; Barker, John J.; Konarev, Alexander V.; Shewry, Peter R.; Clarke, Anthony R.; Brady, R.L.

doi:10.1006/jmbi.1999.2891

Cited by 385 publications

(530 citation statements)

References 29 publications

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“…The three-dimensional structures of the complexes between SFTI-1 and trypsin (PDB identifier 1sfi), between SFTI and the protease domain of matriptase (PDB identifier 3p8f), and between MCoTI-II and trypsin 5 were determined experimentally using x-ray crystallography independently by different research groups (16,34). The three-dimensional structure of MCoTI-II in complex with the protease domain of matriptase was built in this study by homology using Modeler9v11 (35).…”

Section: Molecular Modelingmentioning

confidence: 99%

High-affinity Cyclic Peptide Matriptase Inhibitors

Quimbar

Malik

Sommerhoff

et al. 2013

Journal of Biological Chemistry

130

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Background: Sunflower trypsin inhibitor-1 (SFTI-1) and Momordica cochinchinensis trypsin inhibitor-II (MCoTI-II) are potent protease inhibitors comprising a cyclic backbone. Results: Elucidation of structure-activity relationships for SFTI-1 and MCoTI-II was used to design inhibitors with enhanced inhibitory activity. Conclusion: An analog of MCoTI-II is one of the most potent inhibitors of matriptase. Significance: These results provide a solid basis for the design of selective peptide inhibitors of matriptase with therapeutic potential.

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Section: Molecular Modelingmentioning

confidence: 99%

High-affinity Cyclic Peptide Matriptase Inhibitors

Quimbar

Malik

Sommerhoff

et al. 2013

Journal of Biological Chemistry

130

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“…Understanding such factors is of particular importance as a growing number of new protease inhibitors with a substrate-like binding mode are emerging. Such inhibitors can be derived from combinatorial phage-display libraries (7), extracted from plants (8,9) or designed by protein engineering based on naturally occurring standard mechanism inhibitors or other scaffolds (10 -17).…”

mentioning

confidence: 99%

A Camelid-derived Antibody Fragment Targeting the Active Site of a Serine Protease Balances between Inhibitor and Substrate Behavior

Kromann-Hansen

Oldenburg

Yung

et al. 2016

Journal of Biological Chemistry

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A peptide segment that binds the active site of a serine protease in a substrate-like manner may behave like an inhibitor or a substrate. However, there is sparse information on which factors determine the behavior a particular peptide segment will exhibit. Here, we describe the first x-ray crystal structure of a nanobody in complex with a serine protease. The nanobody displays a new type of interaction between an antibody and a serine protease as it inserts its complementary determining region-H3 loop into the active site of the protease in a substrate-like manner. The unique binding mechanism causes the nanobody to behave as a strong inhibitor as well as a poor substrate. Intriguingly, its substrate behavior is incomplete, as 30 -40% of the nanobody remained intact and inhibitory after prolonged incubation with the protease. Biochemical analysis reveals that an intra-loop interaction network within the complementary determining region-H3 of the nanobody balances its inhibitor versus substrate behavior. Collectively, our results unveil molecular factors, which may be a general mechanism to determine the substrate versus inhibitor behavior of other protease inhibitors.Serine proteases catalyze the hydrolysis of peptide bonds and are involved in numerous physiological processes, including digestion, blood clotting, fibrinolysis, complement activation, and turnover of the extracellular matrix (1). Neutralizing serine protease activity using orthosteric inhibitors, i.e. active site binding inhibitors, has been shown to be a successful therapeutic strategy for a number of pathological conditions, although the similar active site topology in all serine proteases increases the risk of off-target effects. Today, serine protease inhibitors are clinically used for therapy of several diseases, including thrombosis and bleeding disorders (2-4).All serine proteases catalyze the same type of hydrolytic reaction utilizing the same biochemical mechanism. Serine protease-catalyzed hydrolysis of a scissile bond proceeds through a highly conserved mechanism involving two tetrahedral intermediates and an acyl-enzyme complex. The polypeptide substrate is aligned in the active site of the protease interacting with the substrate specificity pockets denoted S1-Sn and S1Ј-SnЈ on the acyl and leaving group side of the scissile bond, respectively (5). The P1 residue of the substrate binds into the S1 pocket, and its carbonyl oxygen atom is inserted into the so-called oxyanion hole (backbone amides of chymotrypsinogen numbering). The catalytic triad (His-57, in the protease generates the required nucleophile for the attack of the hydroxyl group of Ser-195 on the carbonyl group of the P1-P1Ј scissile bond to form the first tetrahedral intermediate and later the acyl-enzyme. Following release of the P1Ј-leaving group, a water molecule performs a second nucleophilic attack, thereby completing the cycle (6).Peptide segments that bind the active site of serine proteases in a substrate-like manner may behave like an inhibitor or substrate. Ho...

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“…Recently, two other small cyclic peptides have been reported in higher organisms. One is SFTI, a cyclic 14-aa trypsin inhibitor from sunflower seeds (12), and the other is RTD-1, an 18-aa tridisulfide peptide from rhesus monkey leukocytes (13). The latter is derived from the cotranslational processing of two related genes by a mechanism that is not yet known, and the biosynthetic origin of the former is unknown.…”

mentioning

confidence: 99%

Biosynthesis and insecticidal properties of plant cyclotides: The cyclic knotted proteins from Oldenlandia affinis

Jennings

West

Waine

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

488

679

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Several members of the Rubiaceae and Violaceae families produce a series of cyclotides or macrocyclic peptides of 29 -31 amino acids with an embedded cystine knot. We aim to understand the mechanism of synthesis of cyclic peptides in plants and have isolated a cDNA clone that encodes the cyclotide kalata B1 as well as three other clones for related cyclotides from the African plant Oldenlandia affinis. The cDNA clones encode prepropeptides with a 20-aa signal sequence, an N-terminal prosequence of 46 -68 amino acids and one, two, or three cyclotide domains separated by regions of about 25 aa. The corresponding cyclotides have been isolated from plant material, indicating that the cyclotide domains are excised and cyclized from all four predicted precursor proteins. The exact processing site is likely to lie on the N-terminal side of the strongly conserved GlyLeuPro or SerLeuPro sequence that flanks both sides of the cyclotide domain. Cyclotides have previously been assigned an antimicrobial function; here we describe a potent inhibitory effect on the growth and development of larvae from the Lepidopteran species Helicoverpa punctigera.

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High-resolution structure of a potent, cyclic proteinase inhibitor from sunflower seeds

Cited by 385 publications

References 29 publications

High-affinity Cyclic Peptide Matriptase Inhibitors

High-affinity Cyclic Peptide Matriptase Inhibitors

A Camelid-derived Antibody Fragment Targeting the Active Site of a Serine Protease Balances between Inhibitor and Substrate Behavior

Biosynthesis and insecticidal properties of plant cyclotides: The cyclic knotted proteins from Oldenlandia affinis

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