Structural basis for multi-specific peptide recognition by the anti-IDH1/2 monoclonal antibody, MsMab-1

Although much is now known about the biological properties of the c-kit receptor and its ligand, stem cell factor (SCF), little is known of the structural basis for the binding and function of this hematopoietic cytokine. By analyzing the activities of chimeric interspecies and homologue muteins and epitope mapping of a monoclonal antibody (MoAb) to the human protein, we have found that three distinct regions of SCF are essential for full biological function. Homologue and interspecies swapping of polypeptide sequences between the amino terminus and G35, between L79 and N97, and between R121 and D128 reduced or eliminated the ability of the chimera to act in synergy with murine granulocyte- macrophage colony-stimulating factor (GM-CSF) to promote hematopoietic colony formation. Moreover, a nonconformation-dependent MoAb that neutralizes human, but not murine SCF, was found to bind to residues within the L79-N97 segment of the human homologue. As these three regions localize to the putative first, third, and fourth helices of the protein, findings remarkably similar to previous studies of cytokines as diverse as growth hormone, GM-CSF, and interleukin (IL)-4, our results suggest that cytokines of multiple classes share a common functional organization.

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Structural Basis for Antigenic Peptide Recognition and Processing by Endoplasmic Reticulum (ER) Aminopeptidase 2

Journal of Biological Chemistry ◽

10.1074/jbc.m115.685909 ◽

2015 ◽

Vol 290 (43) ◽

pp. 26021-26032 ◽

Cited By ~ 46

Author(s):

Anastasia Mpakali ◽

Petros Giastas ◽

Nikolas Mathioudakis ◽

Irene M. Mavridis ◽

Emmanuel Saridakis ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Antigenic Peptide ◽

Structural Basis ◽

Peptide Recognition

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Structural Basis for Activity and Specificity of an Anticoagulant Anti-FXIa Monoclonal Antibody and a Reversal Agent

Structure ◽

10.1016/j.str.2017.12.010 ◽

2018 ◽

Vol 26 (2) ◽

pp. 187-198.e4 ◽

Cited By ~ 3

Author(s):

Lauren K. Ely ◽

Marco Lolicato ◽

Tovo David ◽

Kate Lowe ◽

Yun Cheol Kim ◽

...

Keyword(s):

Monoclonal Antibody ◽

Structural Basis ◽

Reversal Agent

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Structural basis of clade‐specific HIV‐1 neutralization by humanized anti‐V3 monoclonal antibody KD‐247

The FASEB Journal ◽

10.1096/fj.14-252262 ◽

2014 ◽

Vol 29 (1) ◽

pp. 70-80 ◽

Cited By ~ 1

Author(s):

Karen A. Kirby ◽

Yee Tsuey Ong ◽

Atsuko Hachiya ◽

Thomas G. Laughlin ◽

Leslie A. Chiang ◽

...

Keyword(s):

Monoclonal Antibody ◽

Structural Basis ◽

Hiv 1

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A Novel Platelet Small-Molecule Agonist Targeting Glycoprotein Ibalpha.

Blood ◽

10.1182/blood.v114.22.4010.4010 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4010-4010

Author(s):

Jianfeng Yang ◽

Zhi Chen ◽

Weiliang Zhu ◽

Changgeng Ruan

Keyword(s):

Monoclonal Antibody ◽

Platelet Aggregation ◽

Small Molecule ◽

Platelet Adhesion ◽

Conflicts Of Interest ◽

Critical Role ◽

Structural Basis ◽

Terminal Fragment ◽

Von Willebrand

Abstract Abstract 4010 Poster Board III-946 Introduction Interaction of glycoprotein (GP) Ibα with Von Willebrand factor (VWF) plays a critical role in platelet adhesion and signal transduction for αIIbβ3 activation under condition of high shear stress. Methods Based on the crystal structure of platelet GPIbα (PDB:1P9A), virtual screening was employed to identify active compounds. Compounds in SPECS database were docked to VWF binding site on the surface of GPIbα. The screening was carried out with the DOCK4.0 program. The 150 highest-scoring compounds were obtained for further bioassay and those with inhibitory activity of VWF binding to GPIbα were investigated the effect on platelet activation and aggregation. Results We found one compound, designated it as YC148, blocked ristocetin-induced plasma VWF binding to recombinant N-terminal fragment GPIbα (H1-V289) by ELISA method. More interestingly, YC148 did not inhibit ristocetin-induced platelet aggregation, on the contrary, it induced platelet aggregation itself in the absence of exogenous modulators such as ristocetin and botrocetin. A VWF A1 blocking antibody could not block platelet aggregation induced by YC148 despite it completely inhibited ristocetin-induced platelet agglutination. And YC148 also stimulated washed platelet aggregation where VWF was absent in the resuspension buffer. These indicated that the aggregation stimulated by YC148 could not the result from VWF binding. Flow cytomety also showed that YC148 increased P-selectin expression on platelet membrane and promoted monoclonal antibody PAC-1 binding to platelet. The platelet aggregation stimulated by YC148 was inhibited by anti-GPIbα monoclonal antibody AN51 and 6D1. Conclusion A novel exogenous small-molecule agonist was found to activate platelet through binding to GPIbα. It provides us a new tool for investigating platelet GPIb outside-in signaling pathway in platelet adhesion and aggregation. Furthermore, the structure of YC148 may provide a structural basis for developing new hemostatic drugs based on the inhibition of VWF-GPIb interaction. The effect of YC148 on platelet from Bernard-Soulier syndrome or GPIbα N-terminal fragment deficient platelet after in vitro cleavage will be further investigated. Disclosures: No relevant conflicts of interest to declare.

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Structural basis for the species selectivity of a fibrin-specific monoclonal antibody

Biochemistry ◽

10.1021/bi00354a039 ◽

1986 ◽

Vol 25 (6) ◽

pp. 1451-1455 ◽

Cited By ~ 10

Author(s):

Gary R. Matsueda ◽

Michael N. Margolies

Keyword(s):

Monoclonal Antibody ◽

Structural Basis ◽

Specific Monoclonal Antibody ◽

Species Selectivity

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Structural basis of internal peptide recognition by PDZ domains using molecular dynamics simulations

10.1101/575233 ◽

2019 ◽

Author(s):

Neetu Sain ◽

Debasisa Mohanty

Keyword(s):

Pdz Domain ◽

Md Simulations ◽

Open Loop ◽

Structural Basis ◽

Pdz Domains ◽

Peptide Recognition ◽

Interaction Partners ◽

Internal Peptide ◽

Dynamics Simulations ◽

Loop Conformation

AbstractPDZ domains are important peptide recognition modules which usually recognize short C-terminal stretches of their interaction partners, but certain PDZ domains can also recognize internal peptides in the interacting proteins. Due to the scarcity of data on internal peptide recognition and lack of understanding of the mechanistic details of internal peptide recognition, identification of PDZ domains capable of recognizing internal peptides has been a difficult task. Since Par-6 PDZ domain can recognize both C-terminal and internal peptides, we have carried out multiple explicit solvent MD simulations of 1 μs duration on free and peptide bound Par-6 PDZ to decipher mechanistic details of internal peptide recognition. These simulations have been analyzed to identify residues which play a crucial role in internal peptide recognition by PDZ domains. Based on the conservation profile of the identified residues, we have predicted 47 human PDZ domains to be capable of recognizing internal peptides in human. We have also investigated how binding of CDC42 to the CRIB domain adjacent to the Par6 PDZ allosterically modulate the peptide recognition by Par6 PDZ. Our MD simulations on CRIB-Par6_PDZ di-domain in isolation as well as in complex with CDC42, indicate that in absence of CDC42 the adjacent CRIB domain induces open loop conformation of PDZ facilitating internal peptide recognition. On the other hand, upon binding of CDC42 to the CRIB domain, Par6 PDZ adopts closed loop conformation required for recognition of C-terminus peptides. These results provide atomistic details of how binding of interaction partners onto adjacent domains can allosterically regulate substrate binding to PDZ domains. In summary, MD simulations provide novel insights into the modulation of substrate recognition preference of PDZ by specific peptides, adjacent domains and binding of interaction partners at allosteric sites.

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