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The presence of androgen receptor variant 7 (AR-V7) variants becomes a significant hallmark of castration-resistant prostate cancer (CRPC) relapsed from hormonal therapy and is associated with poor survival of CRPC patients because of lacking a ligand-binding domain. Currently, it still lacks an effective agent to target AR-V7 or AR-Vs in general. Here, we showed that a novel class of agents (thailanstatins, TSTs and spliceostatin A analogs) can significantly suppress the expression of AR-V7 mRNA and protein but in a less extent on the full-length AR expression. Mechanistically, TST-D is able to inhibit AR-V7 gene splicing by interfering the interaction between U2AF65 and SAP155 and preventing them from binding to polypyrimidine tract located between the branch point and the 3′ splice site. In vivo, TST-D exhibits a potent tumor inhibitory effect on human CRPC xenografts leading to cell apoptosis. The machinery associated with AR gene splicing in CRPC is a potential target for drugs. Based on their potency in the suppression of AR-V7 responsible for the growth/survival of CRPC, TSTs representing a new class of anti-AR-V agents warrant further development into clinical application. [ABSTRACT FROM AUTHOR]

Acyldepsipeptides ( ADEPs) antibiotics bind to Escherichia coli ClpP mimicking the interactions that the IGL/ F loops in ClpA or ClpX ATPases establish with the hydrophobic pockets surrounding the axial pore of the tetradecamer that the protease forms. ADEP binding induces opening of the gates blocking the axial channel of ClpP and allowing protein substrates to be translocated and hydrolysed in the degradation chamber. To identify the structural determinants stabilizing the open conformation of the axial channel for efficient substrate translocation, we constructed ClpP variants with amino acid substitutions in the N-terminal region that forms the axial gates. We found that adoption of a β-hairpin loop by this region and the integrity of the hydrophobic cluster at the base of this loop are necessary elements for the axial gate to efficiently translocate protein substrates. Analysis of ClpP variants from Bacillus subtilis suggested that the identified structural requirements of the axial channel for efficient translocation are conserved between Gram-positive and Gram-negative bacteria. These findings provide mechanistic insights into the activation of ClpP by ADEPs as well as the gating mechanism of the protease in the context of the ClpAP and ClpXP complexes. [ABSTRACT FROM AUTHOR]

The article presents a comparative analysis of the large conformational change of the pseudomerohedrally twinned monoclinic structure of unfolded free nonactin upon the encapsulation of alkali metal ions. It observes the presence of symmetry-independent half-molecules of nonactin in the asymmetric unit residing on a crystallographic two-fold axis during crystallization. Also observed is the low-temperature high-precision ordered structure of free nonactin possessing an unfolded and more planar geometry but globular when encapsulating a cation.

THE TITLE COMPOUND [SYSTEMATIC NAME: (3S,8aS)-3-isopropyl-hexa-hydro-pyrrolo-[1,2-a]pyrazine-1,4-dione], C(10)H(16)N(2)O(2),, is a newly isolated cyclic dipeptide from Burkholderia thailandensis MSMB43. There are two independent mol-ecules in the asymmetric unit. Two C atoms and their attached H atoms in the five-membered ring of one of the mol-ecules are disordered over two sets of sites in a 0.715 (5):0.285 (5) ratio. The two independent mol-ecules have the same configuration and the absolute configurations of the chiral centers were determined based on the observation of anomalous dispersion. In the crystal, two types of N-H⋯O hydrogen bonds link pairs of independent mol-ecules.

FK228 [systematic name: (1S,4S,7Z,10S,16E,21R)-7-ethyl-idene-4,21-di(propan-2-yl)-2-oxa-12,13-dithia-5,8,20,23-tetra-za--bicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone], C(24)H(36)N(4)O(6)S(2), also known as FR901228, depsipeptide, NSC 630176, romidepsin, and marketed as Istodax by Celgene Corporation, is crystallized from ethyl acetate in P2(1) as compared to the absolute configuration of FK228, first crystallized from methanol in P2(1)2(1)2(1) [Shigematsu et al. (1994 ▶). J. Anti-biot.47, 311-314]. A slight difference is observed between the absolute configuration of FK228 and the present structure. The molecular structure is stabilized by intramolecular N-H⋯O hydrogen bonds. In the crystal, molecules are linked via N-H⋯O hydrogen bonds.

THAILANDEPSIN A [SYSTEMATIC NAME: (E)-(1S,5S,6R,9S,20R)-6-[(2S)-butan-2-yl]-5-hy-droxy-20-[2-(meth-yl-sulfan-yl)eth-yl]-2-oxa-11,12-dithia-7,19,22-triaza-bicyclo-[7.7.6]docosa-15-ene-3,8,18,21-tetra-one], C(23)H(37)N(3)O(6)S(3), is a newly reported [Wang et al. (2011). J. Nat. Prod. doi:10.1021/np200324x] bicyclic depsipeptide that has potent histone deacetyl-ase inhibitory activity and broad-spectrum anti-proliferative activity. The absolute configuration of thailandepsin A has been determined from the anomalous dispersion and the stereochemistry of all chiral C atoms. Intra-molecular N-H⋯O and N-H⋯S hydrogen bonds occur. Inter-molecular N-H⋯O and O-H⋯O hydrogen bonds are observed in the crystal structure.

The title compound, C40H64O12, crystallizes in a pseudomerohedrally twinned primitive monoclinic cell with similar contributions of the two twin components. There are two symmetry-independent half-molecules of nonactin in the asymmetric unit. Each molecule has a pseudo-S4 symmetry and resides on a crystallographic twofold axis; the axes pass through the molecular center of mass and are perpendicular to the plane of the macrocycle. The literature description of the room-temperature structure of nonactin as an order-disorder structure in an orthorhombic unit cell is corrected. We report a low-temperature high-precision ordered structure of ;free' nonactin that allowed for the first time precise determination of its bond distances and angles. It possesses an unfolded and more planar geometry than its complexes with encapsulated Na+, K+, Cs+, Ca2+ or NH4+ cations that exhibit more isometric overall conformations.