Fluorine Substituted Proline Enhances the Tubulin Binding Potential of a Tetrapeptide at the GTP Binding Pocket Causing the Inhibition of Microtubule Motility and an Antimitotic Effect

2021 ◽  
Author(s):  
Batakrishna Jana ◽  
Surajit Barman ◽  
Rajsekhar Roy ◽  
Gaurav Das ◽  
Nabanita Mukherjee ◽  
...  
Keyword(s):  
Binding Pocket ◽  
Binding Potential ◽  
Gtp Binding ◽  
Tubulin Binding ◽  
Antimitotic Effect

scholarly journals Transglutaminase 5 is regulated by guanine–adenine nucleotides1

2004 ◽  
Vol 381 (1) ◽  
pp. 313-319 ◽  
Author(s):  
Eleonora CANDI ◽  
Andrea PARADISI ◽  
Alessandro TERRINONI ◽  
Valentina PIETRONI ◽  
Sergio ODDI ◽  
...  
Keyword(s):  
Amino Acid ◽  
Three Dimensional ◽  
Binding Pocket ◽  
Cross Linking ◽  
Bifunctional Enzyme ◽  
Amino Acid Sequence Alignment ◽  
Gtp Binding ◽  
Epidermal Tissue ◽  
Isopeptide Bonds

Transglutaminases (TGases) are Ca2+-dependent enzymes capable of catalysing transamidation of glutamine residues to form intermolecular isopeptide bonds. Nine distinct TGases have been described in mammals, and two of them (types 2 and 3) are regulated by GTP/ATP. TGase2 hydrolyses GTP and is therefore a bifunctional enzyme. In the present study, we report that TGase5 is also regulated by nucleotides. We have identified the putative TGase5 GTP-binding pocket by comparative amino acid sequence alignment and homology-derived three-dimensional modelling. GTP and ATP inhibit TGase5 cross-linking activity in vitro, and Ca2+ is capable of completely reversing this inhibition. In addition, TGase5 mRNA is not restricted to epidermal tissue, but is also present in different adult and foetal tissues, suggesting a role for TGase5 outside the epidermis. These results reveal the reciprocal actions of Ca2+ and nucleotides with respect to TGase5 activity. Taken together, these results indicate that TGases are a complex family of enzymes regulated by calcium, with at least three of them, namely TGase2, TGase3 and TGase5, also being regulated by ATP and GTP.

scholarly journals Unique GTP-Binding Pocket and Allostery of Uridylate Kinase from a Gram-Negative Phytopathogenic Bacterium

2009 ◽  
Vol 385 (4) ◽  
pp. 1113-1126 ◽  
Author(s):  
Jhe-Le Tu ◽  
Ko-Hsin Chin ◽  
Andrew H.-J. Wang ◽  
Shan-Ho Chou
Keyword(s):  
Binding Pocket ◽  
Phytopathogenic Bacterium ◽  
Gram Negative ◽  
Gtp Binding ◽  
Uridylate Kinase

scholarly journals Novel MAPK/AKT-impairing germline NRAS variant identified in a melanoma-prone family

2021 ◽  
Author(s):  
Kevin M. Brown ◽  
Mai Xu ◽  
Michael Sargen ◽  
Hyunbum Jang ◽  
Mingzhen Zhang ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Binding Pocket ◽  
Pi3k Pathway ◽  
Melanoma Risk ◽  
Mediterranean Populations ◽  
Risk Genes ◽  
1000 Genomes ◽  
Gtp Binding ◽  
The Us

AbstractWhile several high-penetrance melanoma risk genes are known, variation in these genes fail to explain melanoma susceptibility in a large proportion of high-risk families. As part of a melanoma family sequencing study, including 435 families from Mediterranean populations, we identified a novel NRAS variant (c.170A>C, p.D57A) in a melanoma-prone family. This variant is absent in exomes in gnomAD, ESP, UKBiobank, and the 1000 Genomes Project, as well as in 11 273 Mediterranean individuals and 109 melanoma-prone families from the US and Australia. This variant occurs in the GTP-binding pocket of NRAS. Differently from other RAS activating alterations, NRAS D57A expression is unable to activate MAPK-pathway both constitutively and after stimulation but enhances EGF-induced PI3K-pathway signaling in serum starved conditions in vitro. Consistent with in vitro data demonstrating that NRAS D57A does not enrich GTP binding, molecular modeling suggests that the D57A substitution would be expected to impair Mg2+ binding and decrease nucleotide-binding and GTPase activity of NRAS. While we cannot firmly establish NRAS c.170A>C (p.D57A) as a melanoma susceptibility variant, further investigation of NRAS as a familial melanoma gene is warranted.

scholarly journals Unusual Interplay of Two Types of Ras Activators, RasGRP and SOS, Establishes Sensitive and Robust Ras Activation in Lymphocytes

2007 ◽  
Vol 27 (7) ◽  
pp. 2732-2745 ◽  
Author(s):  
Jeroen P. Roose ◽  
Marianne Mollenauer ◽  
Mary Ho ◽  
Tomohiro Kurosaki ◽  
Arthur Weiss
Keyword(s):  
B Lymphocytes ◽  
Feedback Loop ◽  
Binding Pocket ◽  
Lymphocyte Development ◽  
Ras Signaling ◽  
Receptor Stimulation ◽  
Gtp Binding ◽  
Ras Activation ◽  
Low Levels

ABSTRACT Ras activation is crucial for lymphocyte development and effector function. Both T and B lymphocytes contain two types of Ras activators: ubiquitously expressed SOS and specifically expressed Ras guanyl nucleotide-releasing protein (RasGRP). The need for two activators is enigmatic since both are activated following antigen receptor stimulation. In addition, RasGRP1 appears to be dominant over SOS in an unknown manner. The crystal structure of SOS provides a clue: an unusual allosteric Ras-GTP binding pocket. Here, we demonstrate that RasGRP orchestrates Ras signaling in two ways: (i) by activating Ras directly and (ii) by facilitating priming of SOS with RasGTP that binds the allosteric pocket. Priming enhances SOS' in vivo activity and creates a positive RasGTP-SOS feedback loop that functions as a rheostat for Ras activity. Without RasGRP1, initiation of this loop is impaired because SOS' catalyst is its own product (RasGTP)—hence the dominance of RasGRP1. Introduction of an active Ras-like molecule (RasV12C40) in T- and B-cell lines can substitute for RasGRP function and enhance SOS' activity via its allosteric pocket. The unusual RasGRP-SOS interplay results in sensitive and robust Ras activation that cannot be achieved with either activator alone. We hypothesize that this mechanism enables lymphocytes to maximally respond to physiologically low levels of stimulation.

scholarly journals SAR1 paralogs differ biochemically in assembly of the COPII coat

2020 ◽  
Author(s):  
David B. Melville ◽  
Sean Studer ◽  
Randy Schekman
Keyword(s):  
Binding Site ◽  
Membrane Surface ◽  
Binding Pocket ◽  
Small Gtpase ◽  
The Other ◽  
The Novel ◽  
Vesicular Traffic ◽  
Gtp Binding ◽  
Binding Preference ◽  
Lipoprotein Secretion

ABSTRACTCOPII-coated vesicles are the primary mediators of vesicular traffic from the ER to the Golgi apparatus. SAR1 is a small GTPase, which, upon GTP binding, recruits the other COPII proteins to the ER membrane. In mammals, there are two SAR1 paralogs which genetic data suggest may have distinct physiological roles, e.g. in lipoprotein secretion for SAR1B. We identified two clusters of amino acids that have conserved, paralog-specific sequences. One cluster is adjacent to the SAR1 GTP-binding pocket and alters the kinetics of GTP exchange. The other cluster is adjacent to the binding site of COPII components SEC31 and SEC23. We found that the latter cluster confers a SEC23A binding preference to SAR1B over SAR1A. In contrast to SAR1B, SAR1A is prone to oligomerize on a membrane surface. Importantly, in relation to its physiological function, SAR1B, but not SAR1A, can compensate for loss of SAR1B in lipoprotein secretion. The SEC31/SEC23-binding site-adjacent divergent cluster is critical for this function. These data identify the novel paralog-specific function for SAR1B, and provide insights into the mechanisms of large cargo secretion and COPII related diseases.

Interactions of laulimalide, peloruside, and their derivatives with the isoforms of β-tubulin

2013 ◽  
Vol 91 (7) ◽  
pp. 511-517 ◽  
Author(s):  
Melissa M. Gajewski ◽  
Jack A. Tuszynski ◽  
Khaled Barakat ◽  
J. Torin Huzil ◽  
Mariusz Klobukowski
Keyword(s):  
Anticancer Agents ◽  
Quantum Mechanical ◽  
Binding Affinities ◽  
Starting Point ◽  
Mechanical Methods ◽  
Tubulin Isoforms ◽  
Tubulin Binding ◽  
Antimitotic Effect ◽  
Derivatives Of ◽  
Β Tubulin

The investigational anticancer agents laulimalide and peloruside are known to exert an antimitotic effect on cells by binding to β-tubulin. The binding affinities of derivatives of laulimalide and peloruside to all known isoforms of human β-tubulin were calculated using molecular mechanical, molecular dynamical, and quantum mechanical methods. Several of the derivatives are predicted to have improved β-tubulin binding affinities compared to the parent structures. These results can form the starting point for developing laulimalide or peloruside derivatives with greater specificity for the particular β-tubulin isoforms, which are overexpressed in certain tumours.

Targeting cytotoxicity and tubulin polymerization by metal–carbene complexes on a purine tautomer platform

2014 ◽  
Vol 43 (26) ◽  
pp. 9838-9842 ◽  
Author(s):  
Shruti Khanna ◽  
Batakrishna Jana ◽  
Abhijit Saha ◽  
Prashant Kurkute ◽  
Surajit Ghosh ◽  
...  
Keyword(s):  
Binding Site ◽  
Structural Investigation ◽  
Tubulin Polymerization ◽  
Carbene Complexes ◽  
Gtp Binding ◽  
Tubulin Binding ◽  
A Site

This communication describes the synthesis, structural investigation and tubulin binding of purine rare imino tautomer based Ag(i) and Hg(ii)–carbene complexes. These complexes exhibit cytotoxicity through tubulin interaction by binding to a site close to the GTP binding site.

1,8-Naphthalimide derivatives: new leads against dynamin I GTPase activity

2015 ◽  
Vol 13 (29) ◽  
pp. 8016-8028 ◽  
Author(s):  
Mohammed K. Abdel-Hamid ◽  
Kylie A. Macgregor ◽  
Luke R. Odell ◽  
Ngoc Chau ◽  
Anna Mariana ◽  
...  
Keyword(s):  
In Silico ◽  
Binding Pocket ◽  
Gtpase Activity ◽  
Gtp Binding ◽  
Dynamin I

Fragment-basedin silicoscreening against dynamin I (dynI) GTPase activity identified the 1,8-naphthalimide framework as a potential scaffold for the design of new inhibitors targeting the GTP binding pocket of dynI.

scholarly journals West Nile Virus Methyltransferase Catalyzes Two Methylations of the Viral RNA Cap through a Substrate-Repositioning Mechanism

2008 ◽  
Vol 82 (9) ◽  
pp. 4295-4307 ◽  
Author(s):  
Hongping Dong ◽  
Suping Ren ◽  
Bo Zhang ◽  
Yangsheng Zhou ◽  
Francesc Puig-Basagoiti ◽  
...  
Keyword(s):  
West Nile Virus ◽  
Binding Site ◽  
Binding Sites ◽  
Biochemical Analysis ◽  
Rna Binding ◽  
Binding Pocket ◽  
Viral Rna ◽  
West Nile ◽  
Rna Molecules ◽  
Gtp Binding

ABSTRACT Flaviviruses encode a single methyltransferase domain that sequentially catalyzes two methylations of the viral RNA cap, GpppA-RNA→m7GpppA-RNA→m7GpppAm-RNA, by using S-adenosyl-l-methionine (SAM) as a methyl donor. Crystal structures of flavivirus methyltransferases exhibit distinct binding sites for SAM, GTP, and RNA molecules. Biochemical analysis of West Nile virus methyltransferase shows that the single SAM-binding site donates methyl groups to both N7 and 2′-O positions of the viral RNA cap, the GTP-binding pocket functions only during the 2′-O methylation, and two distinct sets of amino acids in the RNA-binding site are required for the N7 and 2′-O methylations. These results demonstrate that flavivirus methyltransferase catalyzes two cap methylations through a substrate-repositioning mechanism. In this mechanism, guanine N7 of substrate GpppA-RNA is first positioned to SAM to generate m7GpppA-RNA, after which the m7G moiety is repositioned to the GTP-binding pocket to register the 2′-OH of the adenosine with SAM, generating m7GpppAm-RNA. Because N7 cap methylation is essential for viral replication, inhibitors designed to block the pocket identified for the N7 cap methylation could be developed for flavivirus therapy.

scholarly journals Bulky “Gatekeeper” Residue Changes the Cosubstrate Specificity of Aminoglycoside 2″-Phosphotransferase IIa

2013 ◽  
Vol 57 (8) ◽  
pp. 3763-3766 ◽  
Author(s):  
Monolekha Bhattacharya ◽  
Marta Toth ◽  
Clyde A. Smith ◽  
Sergei B. Vakulenko
Keyword(s):  
Structural Analysis ◽  
Binding Site ◽  
Antibiotic Susceptibility ◽  
Fold Increase ◽  
Binding Pocket ◽  
Nucleoside Triphosphate ◽  
Atp Binding ◽  
Correct Position ◽  
Gtp Binding ◽  
Susceptibility Profiles

ABSTRACTThe aminoglycoside 2″-phosphotransferases APH(2″)-IIa and APH(2″)-IVa can utilize ATP and GTP as cosubstrates, since both enzymes possess overlapping but discrete structural templates for ATP and GTP binding. APH(2″)-IIIa uses GTP exclusively, because its ATP-binding template is blocked by a bulky tyrosine “gatekeeper” residue. Replacement of the “gatekeeper” residues M85 and F95 in APH(2″)-IIa and APH(2″)-IVa, respectively, by tyrosine does not significantly change the antibiotic susceptibility profiles produced by the enzymes. In APH(2″)-IIa, M85Y substitution results in an ∼10-fold decrease in theKmvalue of GTP and an ∼320-fold increase in theKmvalue of ATP. In APH(2″)-IVa, F95Y substitution results in a modest decrease in theKmvalues of both GTP and ATP. Structural analysis indicates that in the APH(2″)-IIa M85Y mutant, tyrosine blocks access of ATP to the correct position in the binding site, while the larger nucleoside triphosphate (NTP)-binding pocket of the APH(2″)-IVa F95Y mutant allows the tyrosine to move away, thus giving access to the ATP-binding template.

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