This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The chemical synthesis of proteins allows us to understand the chemical basis of protein function in unique ways. Ongoing projects are the following: i. Application of racemic protein crystallography to determine the X-ray structure of protein molecules, which are otherwise difficult to crystallize. Crystallization of a protein molecule from a racemic mixture {i.e. a solution containing equal proportions of L- and D- protein enantiomers} can greatly facilitate the formation of highly ordered centrosymmetric crystals. The availability of centrosymmetric protein crystals can in turn facilitate ab initio structure solution by direct methods. We have recently demonstrated this racemic approach by producing centrosymmeric protein crystals of Snowflee antifreeze protein, antimicrobial microprotein plectasin, omwaprin and several difficult to crystallize ion channel ligands from our laboratory. To explore the general utility of this racemic method we are currently applying this to other chemically synthesized proteins, which are known to be recalcitrant to crystallization in their wild type form alone. The list of protein targets currently being explored in our laboratory includes the largest ever known natural cyclotide palicourein, proinsulin, glycoprotein I-309 and a hypothetical protein from mycobacterium tuberculosis Rv1738. We are also extending this method to obtain crystals from a quasi-racemic mixture of D-protein and an analogue of L-protein. ii. Elucidation of molecular details of HIV-1 protease catalysis, an important target in AIDS chemotherapy. Various chemical analogues have been synthesized to perform 'dynamics/function'correlations in catalytic mechanism as well as totally artificial tunable catalytic apparatus have been designed and incorporated. We are currently using X-ray crystallography to elucidate the molecular details of HIV-1 protease catalysis.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR015301-09
Application #
8361637
Study Section
Special Emphasis Panel (ZRG1-BCMB-K (40))
Project Start
2011-04-01
Project End
2012-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
9
Fiscal Year
2011
Total Cost
$90,695
Indirect Cost
Name
Cornell University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Fallas, Jorge A; Ueda, George; Sheffler, William et al. (2017) Computational design of self-assembling cyclic protein homo-oligomers. Nat Chem 9:353-360
Krotee, Pascal; Rodriguez, Jose A; Sawaya, Michael R et al. (2017) Atomic structures of fibrillar segments of hIAPP suggest tightly mated ?-sheets are important for cytotoxicity. Elife 6:
Dhayalan, Balamurugan; Mandal, Kalyaneswar; Rege, Nischay et al. (2017) Scope and Limitations of Fmoc Chemistry SPPS-Based Approaches to the Total Synthesis of Insulin Lispro via Ester Insulin. Chemistry 23:1709-1716
Bale, Jacob B; Gonen, Shane; Liu, Yuxi et al. (2016) Accurate design of megadalton-scale two-component icosahedral protein complexes. Science 353:389-94
AhYoung, Andrew P; Koehl, Antoine; Vizcarra, Christina L et al. (2016) Structure of a putative ClpS N-end rule adaptor protein from the malaria pathogen Plasmodium falciparum. Protein Sci 25:689-701
Hancock, Stephen P; Stella, Stefano; Cascio, Duilio et al. (2016) DNA Sequence Determinants Controlling Affinity, Stability and Shape of DNA Complexes Bound by the Nucleoid Protein Fis. PLoS One 11:e0150189
Taylor, Noah D; Garruss, Alexander S; Moretti, Rocco et al. (2016) Engineering an allosteric transcription factor to respond to new ligands. Nat Methods 13:177-83
Kattke, Michele D; Chan, Albert H; Duong, Andrew et al. (2016) Crystal Structure of the Streptomyces coelicolor Sortase E1 Transpeptidase Provides Insight into the Binding Mode of the Novel Class E Sorting Signal. PLoS One 11:e0167763
Jorda, J; Leibly, D J; Thompson, M C et al. (2016) Structure of a novel 13 nm dodecahedral nanocage assembled from a redesigned bacterial microcompartment shell protein. Chem Commun (Camb) 52:5041-4
Dhayalan, Balamurugan; Fitzpatrick, Ann; Mandal, Kalyaneswar et al. (2016) Efficient Total Chemical Synthesis of (13) C=(18) O Isotopomers of Human Insulin for Isotope-Edited FTIR. Chembiochem 17:415-20

Showing the most recent 10 out of 402 publications