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Last update 08 May 2025

Pleckstrin homology

Last update 08 May 2025

Basic Info

Synonyms-

Introduction-

Drugs associated with Pleckstrin homology

DM-PIT-1 (Northeastern University)

Target

Pleckstrin homology

Mechanism

Pleckstrin homology modulators

Active Org.-

Originator Org.

Northeastern University

Active Indication-

Inactive Indication

Neoplasms

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with Pleckstrin homology

100 Translational Medicine associated with Pleckstrin homology

0 Patents (Medical) associated with Pleckstrin homology

697

Literatures (Medical) associated with Pleckstrin homology

01 May 2025·International Journal of Biological Macromolecules

Molecular basis of two broad-spectrum antibodies neutralizing rabies virus and other phylogroup-I lyssaviruses by blocking structural transition between the pleckstrin-homology and fusion domains in the glycoprotein

Article

Author: Lin, Sheng ; Yu, Yueru ; Wang, Wei ; Ye, Fei ; Yang, Jing ; Yang, Fanli ; He, Bin ; Lu, Guangwen ; Yin, Keqing ; Cao, Yu ; Zhai, Lili ; Ye, Haoyu ; Gao, Jian ; Chen, Zimin ; Shu, Siqi ; Guo, Liyan

Rabies virus (RABV), the prototype species of the Lyssavirus genus, causes the lethal disease of rabies. Rabies can be efficiently prevented with post-exposure prophylaxis. The RABV glycoprotein (RABV-G) is an essential factor mediating virus entry and the major target of neutralizing antibodies. Here, we report the crystal structures of two neutralizing monoclonal antibodies (NM57 and SOJB) in complex with RABV-G. The two antibodies recognize highly overlapped epitopes involving both the pleckstrin-homology domain (PHD) and the junction between PHD and the fusion domain (FD). Our pseudovirus neutralization assay further shows that both antibodies could neutralize a majority of the lyssaviruses in phylogroup-I. Via sequence comparison and structural characterization, we identify two residues located at positions 226 and 231 in PHD, as key determinants for antibody recognition, which is further corroborated by mutagenesis analyses. Finally, detailed structural analyses reveal that NM57 and SOJB would lock the PHD/FD local structure in the pre-fusion-like state, thereby inhibiting viral infection by blocking structural transitions of RABV-G essential for membrane fusion. Taken together, these results provide a mechanistic glimpse into the molecular basis for broad neutralization of phylogroup-I lyssaviruses by NM57 and SOJB, which should be able to facilitate the development of monoclonal antibodies and vaccines.

01 Apr 2025·Biophysical Journal

Cooperativity of PIP2 and PS lipids modulates PH domain binding

Article

Author: Baiz, Carlos R ; Hudson, Rose B ; Cardenas, Alfredo E ; Senning, Eric N ; Elber, Ron ; Chen, Xiaobing

Phosphatidylinositides constitute only 1%-3% of plasma membranes but play vital roles in cellular signaling. In particular, phosphatidylinositol 4,5-bisphosphate (PIP₂) is involved in processes such as cytoskeleton organization and ion-channel regulation. Pleckstrin homology (PH) domains are modular domains found in many proteins and are known for their strong affinity for PIP₂ headgroups. The role of lipid composition in PH domain binding to PIP₂, particularly the inclusion of phosphatidylserine (PS), is not well understood. This study explores the mechanisms of PH domain binding to PIP₂ using fluorescence spectroscopy, Fourier transform infrared spectroscopy, two-dimensional infrared spectroscopy, and molecular dynamics simulations. We find that anionic PIP₂ and PS alter the interfacial environment compared to phosphatidylcholines. Additionally, the PH domain promotes the localization of anionic lipid domains upon binding. Our results highlight the role of PS in lipid domain formation within membranes and its potential influence on protein binding affinities and lipid geometries. Specifically, we discovered a strong interaction between PIP₂ and PS whereby hydrogen bonding within these anionic lipids drives localization in the membrane. This interaction also regulates protein binding at the membrane interface. Our findings suggest that cooperativity between PIP₂ and PS is key to the formation of localized lipid domains and the recruitment of proteins such as the PH domain of phospholipase C-δ1.

01 Apr 2025·Development, Growth & Differentiation

Establishment and characterization of adap1‐deficient zebrafish

Article

Author: Kawahara, Atsuo ; Fujimaki, Saori ; Kosaki, Kenjiro ; Nishimura, Yuhei ; Yasojima, Sakyo ; Koiwa, Junko ; Ito, Hiroaki ; Yamada, Mamiko

AbstractThe adap1 (ADP‐ribosylation factor GTPase‐activating protein [ArfGAP] with dual pleckstrin homology [PH] domains 1) gene is predominantly expressed in the mouse brain and is important in neural differentiation and development. However, the functions of adap1 in morphogenesis, locomotor activity, and behaviors in vertebrates are not fully understood. Whole‐mount in situ hybridization (WISH) analysis revealed that adap1 was widely expressed in the zebrafish brain, including the forebrain, midbrain, and hindbrain, during early embryogenesis. To investigate the physiological function of the adap1 gene, we generated zebrafish adap1 mutants harboring frameshift mutations around codon 120 of adap1. The adap1 mutants containing homozygous mutant alleles exhibited no apparent morphological abnormalities at 1 day postfertilization (dpf), and the spontaneous coiling and touch response of the adap1 mutants were comparable to those of the wild‐type fish. In addition, the expression of neural genes, such as emx1, mbx, and huC, was comparable between the wild‐type fish and the adap1 mutants at 1 dpf. The adap1 mutants grew to adulthood without exhibiting any apparent swimming defects. The adult adap1 mutants spent more time than the wild type in the center region of the open field test. In the social behavior test, zebrafish containing the adap1 mutant alleles spent more time than the wild type in the regions near the chambers where novel conspecifics swam. These results imply the involvement of the adap1 gene in regulating approach behavior to visual cues from conspecifics.

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Pleckstrin homology

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