FAN Hao

A dual substrate-accessing mechanism of a major facilitator superfamily protein facilitates lysophospholipid flipping across the cell membrane

Published date : 29 Oct 2018

Lysophospholipid transporter (LplT) is a member of the major facilitator superfamily (MFS) present in many Gram-negative bacteria. LplT catalyzes flipping of lysophospholipids (LPLs) across the bacterial inner membrane, playing an important role in bacterial membrane homeostasis. We previously reported that LplT promotes both uptake of exogenous LPLs and intramembranous LPL flipping across the bilayer.

type
Journal Paper
journal
Journal of Biological Chemistry, 2018, October 29, doi: 10.1074/jbc.RA118.005548
Impact Factor
4.01

Identification of FDA-approved drugs as novel allosteric inhibitors of human executioner caspases

Published date : 14 Sep 2018

The regulation of apoptosis is a tightly-coordinated process and caspases are its chief regulators. Of special importance are the executioner caspases, caspase-3/7, the activation of which irreversibly sets the cell on the path of death. Dysregulation of apoptosis, particularly an increased rate of cell death lies at the root of numerous human diseases. Although several peptide-based inhibitors targeting the homologous active site region of caspases have been developed, owing to their non-specific activity and poor pharmacological properties their use has largely been restricted.

type
Journal Paper
journal
Proteins: Structure, Function and Bioinformatics, 2018 Sep 8. doi: 10.1002/prot.25601
Impact Factor
2.274

Structures of the Human PGD2 Receptor CRTH2 Reveal Novel Mechanisms for Ligand Recognition

Published date : 13 Sep 2018

The signaling of prostaglandin D 2 (PGD 2) through G-protein-coupled receptor (GPCR) CRTH2 is a major pathway in type 2 inflammation. Compelling evidence suggests the therapeutic benefits of blocking CRTH2 signaling in many inflammatory disorders. Currently, a number of CRTH2 antagonists are under clinical investigation, and one compound, fevipiprant, has advanced to phase 3 clinical trials for asthma. Here, we present the crystal structures of human CRTH2 with two antagonists, fevipiprant and CAY10471.

type
Journal Paper
journal
Molecular Cell, 2018, doi: 10.1016/j.molcel.2018.08.009
Impact Factor
14.428

Oncogenic activation of STAT3 pathway drives PD-L1 expression in natural killer/T cell lymphoma

Published date : 27 Jul 2018

Mature T-cell lymphomas, including peripheral T-cell lymphoma (PTCL) and extranodal NK/T-cell lymphoma (NKTL), represent a heterogeneous group of non-Hodgkin lymphomas with dismal outcomes and limited treatment options. To determine the extent of involvement of JAK/STAT pathway in this malignancy, we performed targeted capture sequencing of 188 genes in this pathway in 171 PTCL and NKTL cases. A total of 272 non-synonymous somatic mutations in 101 genes were identified in 73% of the samples, including 258 single nucleotide variants and 14 insertions or deletions.

type
Journal Paper
journal
Blood 2018 Jul 27, doi: 10.1182/blood-2018-01-829424
Impact Factor
15.132

author

A benchmarking study on virtual ligand screening against homology models of human GPCRs

Published date : 27 Jul 2018

G-protein-coupled receptor (GPCR) is an important target class of proteins for drug discovery, with over 27% of FDA-approved drugs targeting GPCRs. However, being a membrane protein, it is difficult to obtain the 3D crystal structures of GPCRs for virtual screening of ligands by molecular docking. Thus, we evaluated the virtual screening performance of homology models of human GPCRs with respect to the corresponding crystal structures.

type
Journal Paper
journal
Proteins: Structure, Function, and Bioinformatics, 2018 Jul 27, doi: 10.1002/prot.25533
Impact Factor
2.274

Homozygous mutation in MFSD2A, encoding a lysolipid transporter for docosahexanoic acid, is associated with microcephaly and hypomyelination

Published date : 24 Jul 2018

The major facilitator superfamily domain-containing protein 2A (MFSD2A) is a constituent of the blood-brain barrier and functions to transport lysophosphatidylcholines (LPCs) into the central nervous system. LPCs such as that derived from docosahexanoic acid (DHA) are indispensable to neurogenesis and maintenance of neurons, yet cannot be synthesized within the brain and are dependent on MFSD2A for brain uptake. Recent studies have implicated MFSD2A mutations in lethal and non-lethal microcephaly syndromes, with the severity correlating to the residual activity of the transporter.

type
Journal Paper
journal
Neurogenetics 2018 Jul 24. doi: 10.1007/s10048-018-0556-6
Impact Factor
3.09

Orthosteric and allosteric action of the C5a receptor antagonists

Published date : 11 Jun 2018

The C5a receptor (C5aR) is a G-protein-coupled receptor (GPCR) that can induce strong inflammatory response to the anaphylatoxin C5a. Targeting C5aR has emerged as a novel anti-inflammatory therapeutic method. However, developing potent C5aR antagonists as drugs has proven difficult. Here, we report two crystal structures of human C5aR in ternary complexes with the peptide antagonist PMX53 and a non-peptide antagonist, either avacopan or NDT9513727.

type
Journal Paper
journal
Natural Structural & Molecular Biology, Vol 25, June 2018, Pg 472-481, doi:10.1038/s41594-018-0067-z
Impact Factor
12.595

Biophysical studies and modelling indicate the binding preference of TAZ WW domain for LATS1 PPxY motif

Published date : 30 May 2018

The Hippo tumor suppressor pathway is an important regulator of cell proliferation and apoptosis, and signal transduction occurs through phosphorylation of the effector protein TAZ by the serine/threonine kinase LATS1/2. Here, we report the biophysical and computational studies to characterize the interaction between TAZ and LATS1/2 through WW domain-PPxY motif binding. We show that the TAZ WW domain exhibits a binding preference for the second of the two PPxY motifs of LATS1 in vitro.

type
Journal Paper
journal
Biochemical and Biophysical Research Communications, Vol. 502, Issue 3, 20 Jul 2018, Pg 307-312, PMID: 29787761, doi: 10.1016/j.bbrc.2018.05.127

Impact Factor
2.559

In Silico and in Vitro Interactions between Short Chain Fatty Acids and Human Histone Deacetylases

Published date : 15 Aug 2017

Short chain fatty acids (SCFAs) are postulated to modulate the immune development of neonates via epigenetic regulations such as histone deacetylase (HDAC) inhibition. In the context of atopic diseases, the inhibition of HDAC maintains T-cell homeostasis and induces naïve T-cell differentiation into adaptive Treg, which regulates the production of anti-inflammatory cytokines and suppression of Th2 immune responses.

type
Journal Paper
journal
Biochemistry, 2017, doi: 10.1021/acs.biochem.7b00508
Impact Factor
2.938