This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project has immediate two goals: (i) to implement a simple algorithm for identifying conserved residues from a set of protein structure alignments and, (ii) to identify ways this approach can be used to better understand the coupling between protein structure and function. Our quintessential goal is to understand how proteins deliver biological function, and to be able to modify or engineer new functionality in order to benefit humankind. Briefly, our algorithm overlays a three-dimensional voxel grid on top of a set of proteins that have been structurally aligned by an alignment algorithm such as CE or Dali. The voxels that have a residue from each protein are recorded, and their contents are the conserved residues for this alignment. The voxel grid is then systematically moved along each {x,y,z} axis independently to possibly identify additional conserved residues. Once we have a list of structurally conserved residues, we can focus on: Identification of additional active site/superfamily residues: We have investigated this in the cAMP and the enolase enzyme family/superfamily. Working with the cAMP proteins, we were able to recover a conserved hydrophobic residue on the distant side of the active site pocket. This residue is obscured in the sequence alignment, and was previously only identified by visual inspection (Berman, PNAS 2005). For the enolase family/superfamiy, we were able to recover the existing family/superfamily residues. Identification of residues that may affect enzyme catalysis: We want to investigate the effect of distal residues on enzyme catalysis. For this analysis we used the DHFR superfamily and a diverse set of TIM proteins. Working with the DHFR superfamily, we were able to identify the movable loop region as well as additional residues implicated in the stabilization of the co-enzyme NADPH (Agarwal, PNAS 2002). For the TIM proteins, we identified 2/3 of the residues previously identified from point mutations as having significant effects on catalytic rates (Silverman, PNAS 2001).

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR001081-29
Application #
7367775
Study Section
Special Emphasis Panel (ZRG1-BBCA (01))
Project Start
2006-07-01
Project End
2007-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
29
Fiscal Year
2006
Total Cost
$45,650
Indirect Cost
Name
University of California San Francisco
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Kozak, John J; Gray, Harry B; Garza-López, Roberto A (2018) Relaxation of structural constraints during Amicyanin unfolding. J Inorg Biochem 179:135-145
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Chu, Shidong; Zhou, Guangyan; Gochin, Miriam (2017) Evaluation of ligand-based NMR screening methods to characterize small molecule binding to HIV-1 glycoprotein-41. Org Biomol Chem 15:5210-5219
Portioli, Corinne; Bovi, Michele; Benati, Donatella et al. (2017) Novel functionalization strategies of polymeric nanoparticles as carriers for brain medications. J Biomed Mater Res A 105:847-858
Alamo, Lorenzo; Koubassova, Natalia; Pinto, Antonio et al. (2017) Lessons from a tarantula: new insights into muscle thick filament and myosin interacting-heads motif structure and function. Biophys Rev 9:461-480
Nguyen, Hai Dang; Yadav, Tribhuwan; Giri, Sumanprava et al. (2017) Functions of Replication Protein A as a Sensor of R Loops and a Regulator of RNaseH1. Mol Cell 65:832-847.e4
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Nekouzadeh, Ali; Rudy, Yoram (2016) Conformational changes of an ion-channel during gating and emerging electrophysiologic properties: Application of a computational approach to cardiac Kv7.1. Prog Biophys Mol Biol 120:18-27
Towse, Clare-Louise; Vymetal, Jiri; Vondrasek, Jiri et al. (2016) Insights into Unfolded Proteins from the Intrinsic ?/? Propensities of the AAXAA Host-Guest Series. Biophys J 110:348-361

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