Diversity of Allosteric Regulation in Proteases

Merdanovic, Melisa; Mönig, Timon; Ehrmann, Michael; Kaiser, Markus

doi:10.1021/cb3005935

Cited by 45 publications

(43 citation statements)

References 79 publications

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“…Although allosteric inhibition has not really been studied with regard to anticoagulation, nature tends to exploit allosterism to confer specific regulation and recognition [51]. Allosterism typically offers two advantages: 1) a higher level of specificity and 2) regulation of intrinsic efficiency (k CAT /K M ) [52–54]. With respect to catalytic efficiency, allosterism relies on energetic coupling between the site of binding and the catalytic site.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, allosterism is likely to possess higher selectivity of action because allosteric sites are less conserved [52–54]. It appears that SPGG2’s allosteric mechanism of action is the reason for its selectivity observed against thrombin, factor Xa, factor VIIa/tissue factor, factor IXa, factor XIIa, trypsin, chymotrypsin, plasma kallikrein, APC, and FXIIIa.…”

Section: Discussionmentioning

confidence: 99%

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Allosteric inhibition of factor XIa. Sulfated non-saccharide glycosaminoglycan mimetics as promising anticoagulants

Al‐Horani¹,

Gailani²,

Desai³

2015

Thrombosis Research

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Recent development of sulfated non-saccharide glycosaminoglycan mimetics, especially sulfated pentagalloyl glucopyranoside (SPGG), as potent inhibitors of factor XIa (FXIa) (J. Med. Chem. 2013; 56:867–878 and J. Med. Chem. 2014; 57:4805–4818) has led to a strong possibility of developing a new line of factor XIa-based anticoagulants. In fact, SPGG represents the first synthetic, small molecule inhibitor that appears to bind in site remote from the active site. Considering that allosteric inhibition of FXIa is a new mechanism for developing a distinct line of anticoagulants, we have studied SPGG’s interaction with FXIa with a goal of evaluating its pre-clinical relevance. Comparative inhibition studies with several glycosaminoglycans revealed the importance of SPGG’s non-saccharide backbone. SPGG did not affect the activity of plasma kallikrein, activated protein C and factor XIIIa suggesting that SPGG-based anticoagulation is unlikely to affect other pathways connected with coagulation factors. SPGG’s effect on APTT of citrated human plasma was also not dependent on antithrombin or heparin cofactor II. Interestingly, SPGG’s anticoagulant potential was diminished by serum albumin as well as factor XI, while it could be reversed by protamine or polybrene, which implies possible avenues for developing antidote strategy. Studies with FXIa mutants indicated that SPGG engages Lys529, Arg530 and Arg532, but not Arg250, Lys252, Lys253 and Lys255. Finally, SPGG competes with unfractionated heparin, but not with polyphosphates and/or glycoprotein Ibα, for binding to FXIa. These studies enhance understanding on the first allosteric inhibitor of FXIa and highlight its value as a promising anticoagulant.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Allosteric inhibition of factor XIa. Sulfated non-saccharide glycosaminoglycan mimetics as promising anticoagulants

Al‐Horani¹,

Gailani²,

Desai³

2015

Thrombosis Research

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“…This phenomenon of allostery is central to the function of several critical protein families, including kinases, proteases, G-protein coupled receptors, and transcription factors (Beckett, 2009; Conn, Christopoulos, & Lindsley, 2009; Kornev & Taylor, 2015; Merdanovic, Monig, Ehrmann, & Kaiser, 2013). Indeed, the modification of allosteric mechanisms by naturally occurring mutations or targeted drug binding has been shown to alter cellular networks and is a prominent mechanism for both the cause and treatment of disease (Nussinov & Tsai, 2013; Nussinov, Tsai, & Ma, 2013).…”

Section: Introductionmentioning

confidence: 99%

Detecting Allosteric Networks Using Molecular Dynamics Simulation

Bowerman

Wereszczynski

2016

Methods in Enzymology

126

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Allosteric networks allow enzymes to transmit information and regulate their catalytic activities over vast distances. In principle, molecular dynamics (MD) simulations can be used to reveal the mechanisms that underlie this phenomenon; in practice, it can be difficult to discern allosteric signals from MD trajectories. Here, we describe how MD simulations can be analyzed to reveal correlated motions and allosteric networks, and provide an example of their use on the coagulation enzyme thrombin. Methods are discussed for calculating residue-pair correlations from atomic fluctuations and mutual information, which can be combined with contact information to identify allosteric networks and to dynamically cluster a system into highly correlated communities. In the case of thrombin, these methods show that binding of the antagonist hirugen significantly alters the enzyme’s correlation landscape through a series of pathways between Exosite I and the catalytic core. Results suggest that hirugen binding curtails dynamic diversity and enforces stricter venues of influence, thus reducing the accessibility of thrombin to other molecules.

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“…This analysis led to identification of compound 12n, which showed a 10-fold selectivity toward DPP8 when measuring IC 50 values and a 6.4 selectivity for DPP8 over DPP9 in K i values (36). Allosteric inhibitors are emerging as a promising alternative approach to competitive inhibitors, which are more prone to off-target side effects caused by the high conservation of the catalytic sites (37)(38)(39). Amino acid alignment analysis of DPP8, DPP9, and DPPIV shows a lower conservation of the arm compared with the active site of the DPP enzymes.…”

Section: Discussionmentioning

confidence: 99%

The SUMO1-E67 Interacting Loop Peptide Is an Allosteric Inhibitor of the Dipeptidyl Peptidases 8 and 9

Pilla

Kilisch

Lenz

et al. 2013

Journal of Biological Chemistry

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Background: SUMO1 binds to an arm motif in the prolyl-peptidase DPP9, leading to allosteric activation of the peptidase. Results: A SUMO1 peptide covering the DPP9 interaction surface inhibits DPP9 activity. Inhibition is dependent on residues in the DPP9 arm motif. Conclusion: The SUMO1 peptide and its variants are allosteric DPP9 inhibitors. Significance: This work highlights the potential use of peptides mimicking interaction surfaces for modulating enzyme activity.

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Diversity of Allosteric Regulation in Proteases

Cited by 45 publications

References 79 publications

Allosteric inhibition of factor XIa. Sulfated non-saccharide glycosaminoglycan mimetics as promising anticoagulants

Allosteric inhibition of factor XIa. Sulfated non-saccharide glycosaminoglycan mimetics as promising anticoagulants

Detecting Allosteric Networks Using Molecular Dynamics Simulation

The SUMO1-E67 Interacting Loop Peptide Is an Allosteric Inhibitor of the Dipeptidyl Peptidases 8 and 9

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