Cyclic guanosine 3′,5′‐monophosphate (cGMP) is an intracellular signalling molecule involved in many sensory and developmental processes. Synthesis of cGMP from GTP is catalysed by guanylate cyclase ...(GC) in a reaction analogous to cAMP formation by adenylate cyclase (AC). Although detailed structural information is available on the catalytic region of nucleotidyl cyclases (NCs) in various states, these atomic models do not provide a sufficient explanation for the substrate selectivity between GC and AC family members. Detailed structural information on the GC domain in its active conformation is largely missing, and no crystal structure of a GTP‐bound wild‐type GC domain has been published to date. Here, we describe the crystal structure of the catalytic domain of rhodopsin–GC (RhGC) from Catenaria anguillulae in complex with GTP at 1.7 Å resolution. Our study reveals the organization of a eukaryotic GC domain in its active conformation. We observe that the binding mode of the substrate GTP is similar to that of AC–ATP interaction, although surprisingly not all of the interactions predicted to be responsible for base recognition are present. The structure provides insights into potential mechanisms of substrate discrimination and activity regulation that may be common to all class III purine NCs.
Database
Structural data are available in Protein Data Bank database under the accession number 6SIR.
Enzymes
EC4.6.1.2.
Synthesis of cGMP, an important intracellular signalling molecule, is catalysed by guanylate cyclases. Although detailed structural information is available, current data do not provide a sufficient explanation for the substrate selectivity between guanylate and adenylate cyclases. We present the crystal structure of the GTP‐bound catalytic domain of rhodopsin–GC from Catenaria anguillulae at 1.7 Å resolution. Our study provides insights into potential mechanisms of substrate discrimination and activity regulation.
Centrosome Clustering & Chemotherapy Firdous, Farhat; Raza, Hadeeqa Gull; Chotana, Ghayoor Abbas ...
Mini reviews in medicinal chemistry,
01/2023, Letnik:
23, Številka:
4
Journal Article
Recenzirano
Centrosome abnormalities are the hallmark of cancer. How it affects tumorigenesis is still a mystery. However, the presence of more than two centrosomes at the onset of mitosis often leads to ...chromosomal instability and subsequent tumorigenesis. Unlike normal cells that undergo repair or apoptosis in response to this instability, cancer cells learn to cope with supernumerary centrosomes through various mechanisms and survive. Centrosome clustering is the most prevalent mechanism, allowing the cancer cells to form two daughter cells through a pseudo-bipolar spindle. Since healthy cells are devoid of the mechanisms involved in clustering, the de-clustering of centrosomes can be considered a promising approach to selectively eliminate cells with extra centrosomes. Several proteins such as PARP, KIFC1, Hsp70, Cortical actin, APC/C-CDH1 complex and Eg5 have been discussed in this review which participate in centrosome clustering, and the inhibition of these proteins can facilitate in impeding tumor growth specifically by declustering centrosomes. In this review, we also present the role of the centrosome in the cell cycle, centrosome amplification, clustering mechanism and reported centrosome de-clustering agents to present the current state of work in the field.
Cyclic guanosine 3′,5′‐monophosphate (
cGMP
) is an intracellular signalling molecule involved in many sensory and developmental processes. Synthesis of
cGMP
from
GTP
is catalysed by guanylate ...cyclase (
GC
) in a reaction analogous to
cAMP
formation by adenylate cyclase (
AC
). Although detailed structural information is available on the catalytic region of nucleotidyl cyclases (
NC
s) in various states, these atomic models do not provide a sufficient explanation for the substrate selectivity between
GC
and
AC
family members. Detailed structural information on the
GC
domain in its active conformation is largely missing, and no crystal structure of a
GTP
‐bound wild‐type
GC
domain has been published to date. Here, we describe the crystal structure of the catalytic domain of rhodopsin–
GC
(Rh
GC
) from
Catenaria anguillulae
in complex with
GTP
at 1.7 Å resolution. Our study reveals the organization of a eukaryotic
GC
domain in its active conformation. We observe that the binding mode of the substrate
GTP
is similar to that of
AC
–
ATP
interaction, although surprisingly not all of the interactions predicted to be responsible for base recognition are present. The structure provides insights into potential mechanisms of substrate discrimination and activity regulation that may be common to all class
III
purine NCs.
Database
Structural data are available in Protein Data Bank database under the accession number
6SIR
.
Enzymes
EC4.6.1.2
.
Aurora kinases (Aurora A, B, and C) are a family of serine/threonine kinases that play critical roles during mitotic initiation and progression. Aurora A and B kinases are ubiquitously expressed, and ...their overexpression and/or amplification in many cancers have been associated with poor prognosis. Several inhibitors that target Aurora kinases A, B, or both have been developed during the past decade with efficacy in different in vitro and in vivo models for a variety of cancers. Recent studies have also identified Aurora A as a synthetic lethal target for different tumor suppressors, including RB1, SMARCA4, and ARID1A, which signifies the need for Aurora-A-selective inhibitors. Here, we report the screening of a small library of quinones (nine naphthoquinones, one orthoquinone, and one anthraquinone) in a biochemical assay for Aurora A kinase that resulted in the identification of several quinones as inhibitors. IC50 determination against Aurora A and B kinases revealed the inhibition of both kinases with selectivity toward Aurora A. Two of the compounds, natural quinone naphthazarin (1) and a pseudo anthraquinone, 2-(chloromethyl)quinizarin (11), potently inhibited the proliferation of various cancer cell lines with IC50 values ranging from 0.16 ± 0.15 to 1.7 ± 0.06 and 0.15 ± 0.04 to 6.3 ± 1.8 μM, respectively. Treatment of cancer cells with these compounds for 24 h resulted in abrogated mitosis and apoptotic cell death. Direct binding of both the compounds with Aurora A kinase was also confirmed through STD NMR analysis. Docking studies predicted the binding of both compounds to the ATP binding pocket of Aurora A kinase. We have, therefore, identified quinones as Aurora kinase inhibitors that can serve as a lead for future drug discovery endeavors.
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