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4zq0

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Current revision

crystal structure of Giardia 14-3-3 in complex with the phosphopeptide A8Ap

Structural highlights

4zq0 is a 8 chain structure with sequence from Giardia lamblia P15 and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.1Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

1433_GIAIC Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner (By similarity). Binds with varying affinity to various synthetic phosphopeptides having a consensus binding motif RSX(pS/pT)XP, called mode-1, where X is any residue and pS/pT is a phosphorylated serine/threonine, and to synthetic phosphopeptides having a consensus binding motif Xp(S/T)X1-2-COOH, called mode-3, in which the phosphorylated residue occupies the penultimate C-terminal position in the target protein, but does not bind to their unphosphorylated counterparts (PubMed:19733174). Binds to synthetic human RAF1 phosphopeptides, but not to their unphosphorylated forms. Binds to difopein, a polypeptide containing a phosphorylation-independent binding motif (PubMed:16368691, PubMed:19733174). Involved in encystation (PubMed:19733174). Involved in cell proliferation. Required for actin and tubulin cytoskeletal organization. Regulates actin filament formation and nuclear size (PubMed:28932813).[UniProtKB:P62261]^[1] ^[2] ^[3]

Publication Abstract from PubMed

Giardiasis is a gastrointestinal diarrheal illness caused by the protozoan parasite Giardia duodenalis, which affects annually over 200 million people worldwide. The limited antigiardial drug arsenal and the emergence of clinical cases refractory to standard treatments dictate the need for new chemotherapeutics. The 14-3-3 family of regulatory proteins, extensively involved in protein-protein interactions (PPIs) with pSer/pThr clients, represents a highly promising target. Despite homology with human counterparts, the single 14-3-3 of G. duodenalis (g14-3-3) is characterized by a constitutive phosphorylation in a region critical for target binding, thus affecting the function and the conformation of g14-3-3/clients interaction. However, to approach the design of specific small molecule modulators of g14-3-3 PPIs, structural elucidations are required. Here, we present a detailed computational and crystallographic study exploring the implications of g14-3-3 phosphorylation on protein structure and target binding. Self-Guided Langevin Dynamics and classical molecular dynamics simulations show that phosphorylation affects locally and globally g14-3-3 conformation, inducing a structural rearrangement more suitable for target binding. Profitable features for g14-3-3/clients interaction were highlighted using a hydrophobicity-based descriptor to characterize g14-3-3 client peptides. Finally, the X-ray structure of g14-3-3 in complex with a mode-1 prototype phosphopeptide was solved and combined with structure-based simulations to identify molecular features relevant for clients binding to g14-3-3. The data presented herein provide a further and structural understanding of g14-3-3 features and set the basis for drug design studies.

Molecular Dynamics Simulations and Structural Analysis of Giardia duodenalis 14-3-3 Protein-Protein Interactions.,Cau Y, Fiorillo A, Mori M, Ilari A, Botta M, Lalle M J Chem Inf Model. 2015 Dec 28;55(12):2611-22. doi: 10.1021/acs.jcim.5b00452. Epub, 2015 Nov 19. PMID:26551337^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Lalle M, Salzano AM, Crescenzi M, Pozio E. The Giardia duodenalis 14-3-3 protein is post-translationally modified by phosphorylation and polyglycylation of the C-terminal tail. J Biol Chem. 2006 Feb 24;281(8):5137-48. doi: 10.1074/jbc.M509673200. Epub 2005, Dec 20. PMID:16368691 doi:http://dx.doi.org/10.1074/jbc.M509673200
↑ Lalle M, Bavassano C, Fratini F, Cecchetti S, Boisguerin P, Crescenzi M, Pozio E. Involvement of 14-3-3 protein post-translational modifications in Giardia duodenalis encystation. Int J Parasitol. 2010 Feb;40(2):201-13. doi: 10.1016/j.ijpara.2009.07.010. Epub, 2009 Sep 3. PMID:19733174 doi:http://dx.doi.org/10.1016/j.ijpara.2009.07.010
↑ Krtkova J, Xu J, Lalle M, Steele-Ogus M, Alas GCM, Sept D, Paredez AR. 14-3-3 Regulates Actin Filament Formation in the Deep-Branching Eukaryote Giardia lamblia. mSphere. 2017 Sep 13;2(5). pii: mSphere00248-17. doi: 10.1128/mSphere.00248-17., eCollection 2017 Sep-Oct. PMID:28932813 doi:http://dx.doi.org/10.1128/mSphere.00248-17
↑ Cau Y, Fiorillo A, Mori M, Ilari A, Botta M, Lalle M. Molecular Dynamics Simulations and Structural Analysis of Giardia duodenalis 14-3-3 Protein-Protein Interactions. J Chem Inf Model. 2015 Dec 28;55(12):2611-22. doi: 10.1021/acs.jcim.5b00452. Epub, 2015 Nov 19. PMID:26551337 doi:http://dx.doi.org/10.1021/acs.jcim.5b00452

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4zq0"

Categories: Giardia lamblia P15 | Large Structures | Synthetic construct | Fiorillo A | Ilari A

@@ Line 1: / Line 1: @@
 ==crystal structure of Giardia 14-3-3 in complex with the phosphopeptide A8Ap==
-<StructureSection load='4zq0' size='340' side='right' caption='[[4zq0]], [[Resolution|resolution]] 3.10&Aring;' scene=''>
+<StructureSection load='4zq0' size='340' side='right'caption='[[4zq0]], [[Resolution|resolution]] 3.10&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4zq0]] is a 8 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZQ0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZQ0 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4zq0]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Giardia_lamblia_P15 Giardia lamblia P15] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZQ0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZQ0 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.1&#8491;</td></tr>
-<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4zq0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zq0 OCA], [http://pdbe.org/4zq0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zq0 RCSB], [http://www.ebi.ac.uk/pdbsum/4zq0 PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4zq0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zq0 OCA], [https://pdbe.org/4zq0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4zq0 RCSB], [https://www.ebi.ac.uk/pdbsum/4zq0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4zq0 ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/1433_GIAIC 1433_GIAIC] Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner (By similarity). Binds with varying affinity to various synthetic phosphopeptides having a consensus binding motif RSX(pS/pT)XP, called mode-1, where X is any residue and pS/pT is a phosphorylated serine/threonine, and to synthetic phosphopeptides having a consensus binding motif Xp(S/T)X1-2-COOH, called mode-3, in which the phosphorylated residue occupies the penultimate C-terminal position in the target protein, but does not bind to their unphosphorylated counterparts (PubMed:19733174). Binds to synthetic human RAF1 phosphopeptides, but not to their unphosphorylated forms. Binds to difopein, a polypeptide containing a phosphorylation-independent binding motif (PubMed:16368691, PubMed:19733174). Involved in encystation (PubMed:19733174). Involved in cell proliferation. Required for actin and tubulin cytoskeletal organization. Regulates actin filament formation and nuclear size (PubMed:28932813).[UniProtKB:P62261]<ref>PMID:16368691</ref> <ref>PMID:19733174</ref> <ref>PMID:28932813</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 21: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Fiorillo, A]]
+[[Category: Giardia lamblia P15]]
-[[Category: Ilari, A]]
+[[Category: Large Structures]]
-[[Category: Phosphopeptide binding protein-protein interaction]]
+[[Category: Synthetic construct]]
-[[Category: Signaling protein]]
+[[Category: Fiorillo A]]
+[[Category: Ilari A]]

4zq0

From Proteopedia

Current revision

crystal structure of Giardia 14-3-3 in complex with the phosphopeptide A8Ap

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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