Related ArticlesComparing pharmacophore models derived from crystallography and NMR ensembles.
J Comput Aided Mol Des. 2017 Oct 19;:
Authors: Ghanakota P, Carlson HA
Abstract
NMR and X-ray crystallography are the two most widely used methods for determining protein structures. Our previous study examining NMR versus X-Ray sources of protein conformations showed improved performance with NMR structures when used in our Multiple Protein Structures (MPS) method for receptor-based pharmacophores (Damm, Carlson, J Am Chem Soc 129:8225-8235, 2007). However, that work was based on a single test case, HIV-1 protease, because of the rich data available for that system. New data for more systems are available now, which calls for further examination of the effect of different sources of protein conformations. The MPS technique was applied to Growth factor receptor bound protein 2 (Grb2), Src SH2 homology domain (Src-SH2), FK506-binding protein 1A (FKBP12), and Peroxisome proliferator-activated receptor-? (PPAR-?). Pharmacophore models from both crystal and NMR ensembles were able to discriminate between high-affinity, low-affinity, and decoy molecules. As we found in our original study, NMR models showed optimal performance when all elements were used. The crystal models had more pharmacophore elements compared to their NMR counterparts. The crystal-based models exhibited optimum performance only when pharmacophore elements were dropped. This supports our assertion that the higher flexibility in NMR ensembles helps focus the models on the most essential interactions with the protein. Our studies suggest that the "extra" pharmacophore elements seen at the periphery in X-ray models arise as a result of decreased protein flexibility and make very little contribution to model performance.
PMID: 29047011 [PubMed - as supplied by publisher]
[NMR paper] Unveiling the "Three Finger Pharmacophore" required for p53-MDM2 Inhibition by Saturation Transfer Difference NMR Initial Growth Rates Approach.
Unveiling the "Three Finger Pharmacophore" required for p53-MDM2 Inhibition by Saturation Transfer Difference NMR Initial Growth Rates Approach.
Related Articles Unveiling the "Three Finger Pharmacophore" required for p53-MDM2 Inhibition by Saturation Transfer Difference NMR Initial Growth Rates Approach.
Chemistry. 2016 Feb 11;
Authors: Angulo J, Goffin SA, Gandhi D, Searcey M, Howell LA
Abstract
Inhibitors of the p53-MDM2 protein-protein interaction are emerging as a novel and validated approach to treating cancer. In this work...
nmrlearner
Journal club
0
02-13-2016 02:40 PM
Combining NMR ensembles and molecular dynamics simulations provides more realistic models of protein structures in solution and leads to better chemical shift prediction
Combining NMR ensembles and molecular dynamics simulations provides more realistic models of protein structures in solution and leads to better chemical shift prediction
Abstract While chemical shifts are invaluable for obtaining structural information from proteins, they also offer one of the rare ways to obtain information about protein dynamics. A necessary tool in transforming chemical shifts into structural and dynamic information is chemical shift prediction. In our previous work we developed a method for 4D prediction of protein 1H chemical shifts in which molecular motions, the...
nmrlearner
Journal club
0
02-11-2012 10:31 AM
Protein-ligand docking guided by ligand pharmacophore-mapping experiment by NMR.
Protein-ligand docking guided by ligand pharmacophore-mapping experiment by NMR.
Protein-ligand docking guided by ligand pharmacophore-mapping experiment by NMR.
J Mol Graph Model. 2011 Sep 3;
Authors: Fukunishi Y, Mizukoshi Y, Takeuchi K, Shimada I, Takahashi H, Nakamura H
Abstract
We developed a new protein-ligand docking calculation method using experimental NMR data. Recently, we proposed a novel ligand epitope-mapping experiment, which utilizes the difference between the longitudinal relaxation rates of ligand protons with and...
nmrlearner
Journal club
0
09-24-2011 04:11 PM
A Large-scale Comparison of Computational Models on the Residue Flexibility for NMR-derived Proteinss.
A Large-scale Comparison of Computational Models on the Residue Flexibility for NMR-derived Proteinss.
A Large-scale Comparison of Computational Models on the Residue Flexibility for NMR-derived Proteinss.
Protein Pept Lett. 2011 Sep 20;
Authors: Zhang H, Shi H, Hanlon M
Abstract
As an alternative to X-ray crystallography, nuclear magnetic resonance (NMR) has also emerged as the method of choice for studying both protein structure and dynamics in solution. However, little work using computational models such as Gaussian network model...
nmrlearner
Journal club
0
09-22-2011 04:25 PM
NMR-derived models of amidopyrine and its metabolites in complexes with rabbit cytochrome P450 2B4 reveal a structural mechanism of sequential N-dealkylation.
NMR-derived models of amidopyrine and its metabolites in complexes with rabbit cytochrome P450 2B4 reveal a structural mechanism of sequential N-dealkylation.
NMR-derived models of amidopyrine and its metabolites in complexes with rabbit cytochrome P450 2B4 reveal a structural mechanism of sequential N-dealkylation.
Biochemistry. 2011 Mar 29;50(12):2123-34
Authors: Roberts AG, Sjögren SE, Fomina N, Vu KT, Almutairi A, Halpert JR
To understand the molecular basis of sequential N-dealkylation by cytochrome P450 2B enzymes, we studied the binding of...
[NMR paper] High-quality homology models derived from NMR and X-ray structures of E. coli protein
High-quality homology models derived from NMR and X-ray structures of E. coli proteins YgdK and Suf E suggest that all members of the YgdK/Suf E protein family are enhancers of cysteine desulfurases.
Related Articles High-quality homology models derived from NMR and X-ray structures of E. coli proteins YgdK and Suf E suggest that all members of the YgdK/Suf E protein family are enhancers of cysteine desulfurases.
Protein Sci. 2005 Jun;14(6):1597-608
Authors: Liu G, Li Z, Chiang Y, Acton T, Montelione GT, Murray D, Szyperski T
The structural...
nmrlearner
Journal club
0
11-25-2010 08:21 PM
[NMR paper] SOMO (SOlution MOdeler) differences between X-Ray- and NMR-derived bead models sugges
SOMO (SOlution MOdeler) differences between X-Ray- and NMR-derived bead models suggest a role for side chain flexibility in protein hydrodynamics.
Related Articles SOMO (SOlution MOdeler) differences between X-Ray- and NMR-derived bead models suggest a role for side chain flexibility in protein hydrodynamics.
Structure. 2005 May;13(5):723-34
Authors: Rai N, Nöllmann M, Spotorno B, Tassara G, Byron O, Rocco M
Reduced numbers of frictional/scattering centers are essential for tractable hydrodynamic and small-angle scattering data modeling. We...
Comparing pharmacophore models derived from crystallography and NMR ensembles.
Linear Mode
