scholarly journals The Crystal Structure of a Human PP2A Phosphatase Activator Reveals a Novel Fold and Highly Conserved Cleft Implicated in Protein-Protein Interactions

2006 ◽  
Vol 281 (32) ◽  
pp. 22434-22438 ◽  
Author(s):  
Audur Magnusdottir ◽  
Pål Stenmark ◽  
Susanne Flodin ◽  
Tomas Nyman ◽  
Martin Hammarström ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Protein Interactions ◽  
Protein Protein Interactions

Glycoprotein Ibalpha Inhibitor Complex Crystal Structure at High Resolution.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 774-774
Author(s):  
P.A Mcewan ◽  
Robert K Andrews ◽  
Jonas Emsley
Keyword(s):  
Crystal Structure ◽  
Shear Stress ◽  
Protein Interactions ◽  
Platelet Adhesion ◽  
Peptide Sequence ◽  
Leucine Rich Repeat ◽  
Protein Protein Interactions ◽  
Leucine Rich Repeats ◽  
Von Willebrand ◽  
Complex Crystal

Abstract Abstract 774 Introduction: The platelet Glycoprotein Ib/V/IX (GpIb/V/IX) complex is considered a major target for anticoagulant therapy. The primary function of the receptor is to mediate platelet adhesion to von Willebrand factor (VWF) bound to damaged sub-endothelium. This represents the first critical step for platelet adhesion under conditions of high fluid shear stress. GpIb/V/IX is implicated in a number of thrombotic pathological processes such as stroke or myocardial infarction and the bleeding disorders Bernard-Soulier syndrome, platelet type von Willebrand disease (Pt-VWD) and thrombotic thrombocytopenic purpura. We have successfully determined the structure of the GpIbalpha N-terminal domain in complex with a potent (sub nM) 11meric peptide inhibitor (OS1) of the interaction with VWF. Methods: We have determined the crystal structure to 1.8Å resolution using molecular replacement. Results. The peptide sequence CTERMALHNLC was readily identifiable bound to GpIbalpha between the extended regulatory (R) loop and the concave surface of the leucine rich repeats. The peptide adopts one and a half turns of an alpha-helix and contacts three subsites (S1, S2 and S3). S1 and S2 reside within the leucine rich repeats and S3 has a unique feature as this subsite involves contact with the regulatory R-loop stabilizing it in a well defined conformation with helical character. This loop alters conformation between an extended beta-hairpin in the VWF-A1 bound structure and a more compact largely disordered structure in the unliganded structure. In this regard, the Pt-VWD mutations of GpIbalpha, G233V and M239V, which reside in the R-loop act by inducing a beta-conformation and thus result in a high affinity form of the receptor. Conclusions: These studies provide a strategy for targeting the GpIbalpha-VWF interaction using small molecules or alpha-helical peptides exploiting the GpIbalpha subsites described here and acting allosterically to stabilise a low affinity conformation of the receptor with an alpha helical R-loop. Ligand mimetic peptide complex crystal structures for the platelet receptors integrin aIIbb3 with RGD, and alpha2beta1 with a collagen peptide have been described and the former are currently in therapeutic use for treatment of thromboemboletic disorders. Targeting the GpIbalpha-VWF interaction may provide anti-thrombotic drugs which affect platelet adhesion under high shear stress without compromising normal processes of platelet adhesion and aggregation which may be required for normal hemostasis to function. Targeting protein-protein interactions is considered one of the great contemporary challenges in drug discovery. The understanding of how the S1S2S3 subsites provide very effective inhibition of a large protein-protein interaction has wide applicability. LRR proteins are an extended family mediating protein-protein interactions involved in a variety of disease processes such as sepsis, asthma, immunodeficiencies, atherosclerosis, alzheimers (leucine rich repeat kinase) and leukaemia (leucine rich repeat phosphatase). The structural fit of the helical curvature of the peptide with the arc of the leucine rich repeats may provide a basis for further development of alpha-helical peptide mimetics targeting other members of the LRR family which utilize the concave face. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Thyroid stimulating autoantibody M22 mimics TSH binding to the TSH receptor leucine rich domain: a comparative structural study of protein–protein interactions

2009 ◽  
Vol 42 (5) ◽  
pp. 381-395 ◽  
Author(s):  
R Núñez Miguel ◽  
J Sanders ◽  
D Y Chirgadze ◽  
J Furmaniak ◽  
B Rees Smith
Keyword(s):  
Crystal Structure ◽  
Protein Interactions ◽  
Hydrophobic Interactions ◽  
Human Monoclonal Antibody ◽  
Tsh Receptor ◽  
Salt Bridges ◽  
Protein Protein Interactions ◽  
Rich Domain ◽  
Candidate Target ◽  
Comparative Model

The TSH receptor (TSHR) ligands M22 (a thyroid stimulating human monoclonal antibody) and TSH, bind to the concave surface of the leucine rich repeats domain (LRD) of the TSHR and here, we show that M22 mimics closely the binding of TSH. We compared interactions produced by M22 with the TSHR in the M22–TSHR crystal structure (2.55 Å resolution) and produced by TSH with the TSHR in a TSH–TSHR comparative model. The crystal structure of the TSHR and a comparative model of TSH based on the crystal structure of FSH were used as components to build the TSH–TSHR model. This model was built based on the FSH–FSH receptor structure (2.9 Å) and then the structure of the TSHR in the model was replaced by the TSHR crystal structure. The analysis shows that M22 light chain mimics the TSHβ chain in its interaction with TSHR LRD, while M22 heavy chain mimics the interactions of the TSHα chain. The M22–TSHR complex contains a greater number of hydrogen bonds and salt bridges and fewer hydrophobic interactions than the TSH–TSHR complex, consistent with a higher M22 binding affinity. Furthermore, the surface area formed by TSHR residues N208, Q235, R255, and N256 has been identified as a candidate target region for small molecules which might selectively block binding of autoantibodies to the TSHR.

scholarly journals The Crystal Structure of Klebsiella pneumoniae FeoA Reveals a Site For Protein-Protein Interactions

2019 ◽  
Author(s):  
Richard O. Linkous ◽  
Alexandrea E. Sestok ◽  
Aaron T. Smith
Keyword(s):  
Crystal Structure ◽  
Klebsiella Pneumoniae ◽  
Protein Interactions ◽  
Pathogenic Bacteria ◽  
Protein Protein Interactions ◽  
Anaerobic Conditions ◽  
Small Peptide ◽  
Host Environment ◽  
Partner Protein ◽  
A Site

ABSTRACTIn order to establish infection, pathogenic bacteria must obtain essential nutrients such as iron. Under acidic and/or anaerobic conditions, most bacteria utilize the Feo system in order to acquire ferrous iron (Fe2+) from their host environment. The mechanism of this process, including its regulation, remains poorly understood. In this work, we have determined the crystal structure of FeoA from the nosocomial agent Klebsiella pneumoniae (KpFeoA). Our structure reveals an SH3-like domain that mediates interactions between neighboring polypeptides via intercalations into a Leu zipper motif. Using docking of a small peptide corresponding to a postulated FeoB partner binding site, we demonstrate the KpFeoA can assume both ‘open’ and ‘closed’ conformations, controlled by peptide binding. We propose a model in which a ‘C-shaped’ clamp along the FeoA surface mediates interactions with its partner protein, FeoB. These findings are the first to demonstrate atomic-level details of FeoA-based protein-protein interactions, which could be exploited for future antibiotic developments.

Complex structure of the acyltransferase VinK and the carrier protein VinL with a pantetheine cross-linking probe

2021 ◽  
Vol 77 (9) ◽  
pp. 294-302
Author(s):  
Akimasa Miyanaga ◽  
Risako Ouchi ◽  
Fumitaka Kudo ◽  
Tadashi Eguchi
Keyword(s):  
Crystal Structure ◽  
Protein Interactions ◽  
Fatty Acid Biosynthesis ◽  
Structural Information ◽  
Complex Structure ◽  
Cross Linking ◽  
Carrier Protein ◽  
Protein Protein Interactions ◽  
Interaction Interface ◽  
Covalent Complex

Acyltransferases are responsible for the selection and loading of acyl units onto carrier proteins in polyketide and fatty-acid biosynthesis. Despite the importance of protein–protein interactions between the acyltransferase and the carrier protein, structural information on acyltransferase–carrier protein interactions is limited because of the transient interactions between them. In the biosynthesis of the polyketide vicenistatin, the acyltransferase VinK recognizes the carrier protein VinL for the transfer of a dipeptidyl unit. The crystal structure of a VinK–VinL covalent complex formed with a 1,2-bismaleimidoethane cross-linking reagent has been determined previously. Here, the crystal structure of a VinK–VinL covalent complex formed with a pantetheine cross-linking probe is reported at 1.95 Å resolution. In the structure of the VinK–VinL–probe complex, the pantetheine probe that is attached to VinL is covalently connected to the side chain of the mutated Cys106 of VinK. The interaction interface between VinK and VinL is essentially the same in the two VinK–VinL complex structures, although the position of the pantetheine linker slightly differs. This structural observation suggests that interface interactions are not affected by the cross-linking strategy used.

scholarly journals Crystal structure of XCC3289 from Xanthomonas campestris: homology with the N-terminal substrate-binding domain of Lon peptidase

2020 ◽  
Vol 76 (10) ◽  
pp. 488-494
Author(s):  
Rahul Singh ◽  
Sonali Deshmukh ◽  
Ashwani Kumar ◽  
Venuka Durani Goyal ◽  
Ravindra D. Makde
Keyword(s):  
Crystal Structure ◽  
Protein Interactions ◽  
Xanthomonas Campestris ◽  
Protein Quality ◽  
Specific Protein ◽  
Protein Protein Interactions ◽  
Homologous Proteins ◽  
Terminal Domain ◽  
Α Helix ◽  
Terminal Domains

LonA peptidase is a major component of the protein quality-control mechanism in both prokaryotes and the organelles of eukaryotes. Proteins homologous to the N-terminal domain of LonA peptidase, but lacking its other domains, are conserved in several phyla of prokaryotes, including the Xanthomonadales order. However, the function of these homologous proteins (LonNTD-like proteins) is not known. Here, the crystal structure of the LonNTD-like protein from Xanthomonas campestris (XCC3289; UniProt Q8P5P7) is reported at 2.8 Å resolution. The structure was solved by molecular replacement and contains one polypeptide in the asymmetric unit. The structure was refined to an R free of 29%. The structure of XCC3289 consists of two domains joined by a long loop. The N-terminal domain (residues 1–112) consists of an α-helix surrounded by β-sheets, whereas the C-terminal domain (residues 123–193) is an α-helical bundle. The fold and spatial orientation of the two domains closely resembles those of the N-terminal domains of the LonA peptidases from Escherichia coli and Mycobacterium avium. The structure is also similar to that of cereblon, a substrate-recognizing component of the E3 ubiquitin ligase complex. The N-terminal domains of both LonA and cereblon are known to be involved in specific protein–protein interactions. This structural analysis suggests that XCC3289 and other LonNTD-like proteins might also be capable of such protein–protein interactions.

scholarly journals The first structure in a family of peptidase inhibitors reveals an unusual Ig-like fold

F1000Research ◽  
2013 ◽  
Vol 2 ◽  
pp. 154 ◽  
Author(s):  
Daniel J Rigden ◽  
Qingping Xu ◽  
Yuanyuan Chang ◽  
Ruth Y Eberhardt ◽  
Robert D Finn ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Cell Surface ◽  
Protein Interactions ◽  
Active Site ◽  
Common Ancestor ◽  
Recent Common Ancestor ◽  
Signal Peptides ◽  
Protein Protein Interactions ◽  
Peptidase Inhibitors ◽  
Structure Solution

We report the crystal structure solution of the Intracellular Protease Inhibitor (IPI) protein from Bacillus subtilis, which has been reported to be an inhibitor of the intracellular subtilisin Isp1 from the same organism. The structure of IPI is a variant of the all-beta, immunoglobulin (Ig) fold. It is possible that IPI is important for protein-protein interactions, of which inhibition of Isp1 is one. The intracellular nature of ISP is questioned, because an alternative ATG codon in the ipi gene would produce a protein with an N-terminal extension containing a signal peptide. It is possible that alternative initiation exists, producing either an intracellular inhibitor or a secreted form that may be associated with the cell surface.  Homologues of the IPI protein from other species are multi-domain proteins, containing signal peptides and domains also associated with the bacterial cell-surface. The cysteine peptidase inhibitors chagasin and amoebiasin also have Ig-like folds, but their topology differs significantly from that of IPI, and they share no recent common ancestor. A model of IPI docked to Isp1 shows similarities to other subtilisin:inhibitor complexes, particularly where the inhibitor interacts with the peptidase active site.

scholarly journals Crystal Structure of PAV1-137: A Protein from the Virus PAV1 That InfectsPyrococcus abyssi

Archaea ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-5
Author(s):  
N. Leulliot ◽  
S. Quevillon-Cheruel ◽  
M. Graille ◽  
C. Geslin ◽  
D. Flament ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Focal Adhesion ◽  
Protein Interactions ◽  
Unknown Function ◽  
Structural Studies ◽  
Protein Protein Interactions ◽  
Helical Bundle ◽  
Putative Protein ◽  
The Family ◽  
Pyrococcus Abyssi

Pyrococcus abyssivirus 1 (PAV1) was the first virus particle infecting a hyperthermophilic Euryarchaeota (Pyrococcus abyssistrain GE23) that has been isolated and characterized. It is lemon shaped and is decorated with a short fibered tail. PAV1 morphologically resembles the fusiform members of the family Fuselloviridae or the genusSalterprovirus. The 18 kb dsDNA genome of PAV1 contains 25 predicted genes, most of them of unknown function. To help assigning functions to these proteins, we have initiated structural studies of the PAV1 proteome. We determined the crystal structure of a putative protein of 137 residues (PAV1-137) at a resolution of 2.2 Å. The protein forms dimers both in solution and in the crystal. The fold of PAV1-137 is a four-α-helical bundle analogous to those found in some eukaryotic adhesion proteins such as focal adhesion kinase, suggesting that PAV1-137 is involved in protein-protein interactions.

scholarly journals Crystal structure of the proximal BAH domain of the polybromo protein

2005 ◽  
Vol 389 (3) ◽  
pp. 657-664 ◽  
Author(s):  
Antony W. Oliver ◽  
Sarah A. Jones ◽  
Stephen Mark Roe ◽  
Steve Matthews ◽  
Graham H. Goodwin ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Protein Interactions ◽  
Nuclear Protein ◽  
Molecular Function ◽  
Protein Protein Interactions ◽  
Chromatin Remodelling Complex ◽  
Hmg Box ◽  
Wide Range ◽  
Bah Domain ◽  
Repeated Motif

The BAH domain (bromo-associated homology domain) was first identified from a repeated motif found in the nuclear protein polybromo – a large (187 kDa) modular protein comprising six bromodomains, two BAH domains and an HMG box. To date, the BAH domain has no ascribed function, although it is found in a wide range of proteins that contain additional domains involved in either transcriptional regulation (e.g. SET, PHD and bromodomain) and/or DNA binding (HMG box and AT hook). The molecular function of polybromo itself also remains unclear, but it has been identified as a key component of an SWI/SNF (switching/sucrose non-fermenting)-related, ATP-dependent chromatin-remodelling complex PBAF (polybromo, BRG1-associated factors; also known as SWI/SNF-B or SWI/SNFβ). We present in this paper the crystal structure of the proximal BAH domain from chicken polybromo (BAH1), at a resolution of 1.6 Å (1 Å=0.1 nm). Structure-based sequence analysis reveals several features that may be involved in mediating protein–protein interactions.

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