Crystal Structure of a Ternary Complex between Human Prostate-specific Antigen, Its Substrate Acyl Intermediate and an Activating Antibody

Ménez, R.; Michel, Sandrine; Müller, Bruno; Bossus, Marc; Ducancel, Frédéric; Jolivet-Reynaud, Colette; Stura, E.A.

doi:10.1016/j.jmb.2007.11.052

Cited by 78 publications

(78 citation statements)

References 32 publications

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“…In this study we explore the possibility of using mAbs as an alternative approach to obtain information about structural features determining the activity of FVIIa. The literature covering antibodies that induce catalytic activity of serine proteases is limited (21)(22)(23)(24). We describe the isolation and characterization of two groups of mAbs capable of enhancing the intrinsic activity of FVIIa.…”

Section: Blood Coagulation Factor VII (Fvii)mentioning

confidence: 99%

Antibody-induced Enhancement of Factor VIIa Activity through Distinct Allosteric Pathways

Andersen

Andreasen

Svendsen

et al. 2012

Journal of Biological Chemistry

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Background:The enzymatic activity of coagulation factor VIIa (FVIIa) is allosterically controlled by tissue factor (TF). Results: Monoclonal antibodies (mAbs) can allosterically augment the intrinsic activity of FVIIa through mechanisms distinct from that of TF. Conclusion: Different modes of allosteric activation of FVIIa appear to exist. Significance: Artificial activators of FVIIa can be tools to study the zymogen-to-protease transition.

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Section: Blood Coagulation Factor VII (Fvii)mentioning

confidence: 99%

Antibody-induced Enhancement of Factor VIIa Activity through Distinct Allosteric Pathways

Andersen

Andreasen

Svendsen

et al. 2012

Journal of Biological Chemistry

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“…Analyses of human urinary and seminal KLK3 samples corroborated varying N-glycosylation and O-glycosylation, which had a significant effect on the enzymatic activity against even small substrates, such as suc-Leu-Leu-Val-Tyr-AMC (Shibata et al, 1997). Whereas one KLK3 crystal structure (2ZCH, Figure 3) exhibited only two GlcNAc molecules linked to Asn61, another structure (3QUM) showed a triantennary N-glycan with terminal sialic acids and a mucin-type O-glycan (GlcNAc-Gal) at Thr125 (Menez et al, 2008;Stura et al, 2011). Similar to seminal KLK3, non-glycosylated KLK3 from E. coli expression reacts with anti-chymotrypsin.…”

Section: The Prostatic Klks 2 Andmentioning

confidence: 99%

Sweetened kallikrein-related peptidases (KLKs): glycan trees as potential regulators of activation and activity

Guo

Skala

Magdolen

et al. 2014

Biological Chemistry

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Most kallikrein-related peptidases (KLKs) are N-glycosylated with N-acetylglucosamine 2 -mannose 9 units at Asn-Xaa-Ser/Thr sequons during protein synthesis and translocation into the endoplasmic reticulum. These N-glycans are modified in the Golgi machinery, where additional O-glycosylation at Ser and Thr takes place, before exocytotic release of the KLKs into the extracellular space. Sequons are present in all 15 members of the KLKs and comparative studies for KLKs from natural and recombinant sources elucidated some aspects of glycosylation. Although glycosylation of mammalian KLKs 1, 3, 4, 6, and 8 has been analyzed in great detail, e.g., by crystal structures, the respective function remains largely unclear. In some cases, altered enzymatic activity was observed for KLKs upon glycosylation. Remarkably, for KLK3/PSA, changes in the glycosylation pattern were observed in samples of benign prostatic hyperplasia and prostate cancer with respect to healthy individuals. Potential functions of KLK glycosylation in structural stabilization, protection against degradation, and activity modulation of substrate specificity can be deduced from a comparison with other glycosylated proteins and their regulation. According to the new concept of protein sectors, glycosylation distant from the active site might significantly influence the activity of proteases. Novel pharmacological approaches can exploit engineered glycans in the therapeutical context.

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“…An important characteristic of KLK3 is that two different conformations can be adapted by the 11-amino acid kallikrein loop, which can acquire either a closed or an open conformation that leads to either mature intact KLK3 with no enzymatic activity or enzymatically active KLK3, respectively. Conversion of the inactive (closed) to active (open) KLK3 conformation can be achieved by high salt concentration or by monoclonal antibodies that capture and stabilize active KLK3, as modeled recently (21).…”

Section: Structure and Activitymentioning

confidence: 99%

Functional Roles of Human Kallikrein-related Peptidases

Sotiropoulou

Pampalakis

Diamandis

2009

Journal of Biological Chemistry

197

194

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Kallikrein-related peptidases constitute a single family of 15 (chymo)trypsin-like proteases (KLK1-15) with pleiotropic physiological roles. Aberrant regulation of KLKs has been associated with diverse diseases such as hypertension, renal dysfunction, skin disorders, inflammation, neurodegeneration, and cancer. Recent studies suggested that coordinated activation and regulation of KLK activity are achieved via a complex network of interactions referred to as the "KLK activome." However, it remains to be validated whether these hypothetical KLK activation cascade pathways are operative in vivo. In addition, KLKs have emerged as versatile signaling molecules. In summary, KLKs represent attractive biomarkers for clinical applications and potential therapeutic targets for common human pathologies.

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Crystal Structure of a Ternary Complex between Human Prostate-specific Antigen, Its Substrate Acyl Intermediate and an Activating Antibody

Cited by 78 publications

References 32 publications

Antibody-induced Enhancement of Factor VIIa Activity through Distinct Allosteric Pathways

Antibody-induced Enhancement of Factor VIIa Activity through Distinct Allosteric Pathways

Sweetened kallikrein-related peptidases (KLKs): glycan trees as potential regulators of activation and activity

Functional Roles of Human Kallikrein-related Peptidases

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