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001-es BibID:	BIBFORM108790
035-os BibID:	(Scopus)85148381582 (WoS)000944102100001
Első szerző:	Hoffka Gyula (vegyész)
Cím:	Self-inhibited state of Venezuelan equine encephalitis virus (VEEV) nsP2 cysteine protease : a crystallographic and molecular dynamics analysis / Gyula Hoffka, George T. Lountos, Danielle Needle, Alexander Wlodawer, David S. Waugh, József Tőzsér, János András Mótyán
Dátum:	2023
ISSN:	0022-2836
Megjegyzések:	The Venezuelan equine encephalitis virus (VEEV) belongs to the Togaviridae family and is pathogenic to both humans and equines. The VEEV non-structural protein 2 (nsP2) is a cysteine protease (nsP2pro) that processes the polyprotein and thus it is a drug target for inhibitor discovery. The atomic structure of the VEEV nsP2 catalytic domain was previously characterized by both X-ray crystallography and computational studies. A modified nsP2pro harboring a N475A mutation in the N terminus was observed to exhibit an unexpected conformation: the N-terminal residues bind to the active site, mimicking binding of a substrate. The large conformational change of the N terminus was assumed to be induced by the N475A mutation, as N475 has an important role in stabilization of the N terminus and the active site. This conformation was first observed in the N475A mutant, but we also found it while determining a crystal structure of the catalytically active nsP2pro containing the wild-type N475 active site residue and K741A/K767A surface entropy reduction mutations. This suggests that the N475A mutation is not a prerequisite for self-inhibition. Here, we describe a high resolution (1.46 ?A) crystal structure of a truncated nsP2pro (residues 463-785, K741A/K767A) and analyze the structure further by molecular dynamics to study the active and self-inhibited conformations of nsP2pro and its N475A mutant. A comparison of the different conformations of the N-terminal residues sheds a light on the interactions that play an important role in the stabilization of the enzyme.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk Venezuelan equine encephalitis virus protease alphavirus crystallography molecular dynamics
Megjelenés:	Journal Of Molecular Biology. - 435 : 6 (2023), p. 1-20. -
További szerzők:	Lountos, George T. Needle, Danielle Wlodawer, Alexander Waugh, David S. Tőzsér József (1959-) (molekuláris biológus, biokémikus, vegyész) Mótyán János András (1981-) (biokémikus, molekuláris biológus)
Pályázati támogatás:	TKP2021-EGA-20 (Biotechnology) Egyéb
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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001-es BibID:	BIBFORM038084
Első szerző:	Matúz Krisztina (vegyész, biokémikus)
Cím:	Inhibition of XMRV and HIV-1 proteases by pepstatin A and acetyl-pepstatin / Matúz Krisztina, Mótyán János András, Li Mi, Wlodawer Alexander, Tőzsér József
Dátum:	2012
Megjegyzések:	The kinetic properties of two classical inhibitors of aspartic proteases (PRs), pepstatin A and acetyl-pepstatin, were compared in their interactions with HIV-1 and xenotropic murine leukemia virus related virus (XMRV) PRs. Both compounds are substantially weaker inhibitors of XMRV PR than of HIV-1 PR. Previous kinetic and structural studies characterized HIV-1 PR-acetyl-pepstatin and XMRV PR-pepstatin A complexes and suggested dramatically different binding modes. Interaction energies were calculated for the possible binding modes and suggested a strong preference for the one-inhibitor binding mode for HIV-1 PR-acetyl-pepstatin and the two-inhibitor binding mode for XMRV PR-pepstatin A interactions. Comparison of the molecular models suggested that in the case of XMRV PR the relatively unfavorable interactions at S3' and the favorable interactions at S4 and S4' sites with the statine residues may shift the ground state binding towards the two-inhibitor binding mode, whereas the single molecule ground state binding of statines to the HIV-1 PR appear to be more favorable. The preferred single molecular binding to HIV-1 PR allows the formation of the transition state complex, represented by substantially better binding constants. Intriguingly, the crystal structure of the complex of acetyl-pepstatin with XMRV PR has shown a mixed type of binding: the unusual binding mode of two molecules of the inhibitor to the enzyme, in a mode very similar to the previously determined complex with pepstatin A, together with the classical binding mode found for HIV-1 PR. The structure is thus in good agreement with the very similar interaction energies calculated for the two types of binding.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban XMRV protease
Megjelenés:	FEBS Journal. - 279 : 17 (2012), p. 3276-3286. -
További szerzők:	Mótyán János András (1981-) (biokémikus, molekuláris biológus) Li, Mi Wlodawer, Alexander Tőzsér József (1959-) (molekuláris biológus, biokémikus, vegyész)
Internet cím:	DOI Intézményi repozitóriumban (DEA) tárolt változat
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