Positions

Overview

  • Dr. Rama Krishna is a Professor in the Department of Biochemistry and Molecular Genetics. He received his Ph.D. from the Indian Institute of Technology-Kanpur in India. He is the Director of the NMR Core Facility and holds joint appointments in the Comprehensive Cancer Center and the Departments of Chemistry and Physics. He was a Leukemia Society of America Scholar during 1982-87. His research program is supported at various times by grants from the NIH, NSF, American Heart Association, Arthritis Foundation and the Leukemia Society of America.
  • Selected Publications

    Academic Article

    Year Title Altmetric
    2016 Identification of initial leads directed at the calmodulin-binding region on the Src-SH2 domain that exhibit anti-proliferation activity against pancreatic cancer 2016
    2013 Identification of the binding site of an allosteric ligand using STD-NMR, docking, and CORCEMA-ST calculations 2013
    2012 1H, 15N, and 13C resonance assignments for a monomeric mutant of the HIV-1 capsid protein 2012
    2011 Structure of a monomeric mutant of the HIV-1 capsid protein 2011
    2011 Structure and lipid interactions of an anti-inflammatory and anti-atherogenic 10-residue class G* apolipoprotein J peptide using solution NMR 2011
    2008 Effect of leucine to phenylalanine substitution on the nonpolar face of a class A amphipathic helical peptide on its interaction with lipid: High resolution solution NMR studies of 4F-dimyristoylphosphatidylcholine discoidal complex 2008
    2008 Quantitative analysis of STD-NMR spectra of reversibly forming ligand-receptor complexes 2008
    2008 Solution structure of a calmodulin-binding domain in the carboxy-terminal region of HIV type 1 gp160 2008
    2008 NMR experiments reveal the molecular basis of receptor recognition by a calicivirus 2008
    2008 Solution structure of a double mutant of the carboxy-terminal dimerization domain of the HIV-1 capsid protein 2008
    2007 Design and development of water-soluble curcumin conjugates as potential anticancer agents 2007
    2006 Association of a model class A (apolipoprotein) amphipathic α helical peptide with lipid: High resolution NMR studies of peptide-lipid discoidal complexes 2006
    2006 Expression of functional scorpion neurotoxin Lqq-V in E.coli 2006
    2005 Determination of the conformation of trimethoprim in the binding pocket of bovine dihydrofolate reductase from a STD-NMR intensity-restrained CORCEMA-ST optimization 2005
    2005 Erratum: Refinement of the conformation of UDP - Galactose bound to galactosyltransferase using the STD NMR intensity-restrained CORCEMA optimization (Journal of The American Chemical Society (2004) 126 (8610-8611)) 2005
    2004 Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in ubiquitin proteasome degradation 2004
    2004 Novel oligosaccharide side chains of the collagen-like region of BclA, the major glycoprotein of the Bacillus anthracis exosporium 2004
    2004 Refinement of the conformation of UDP-galactose bound to galactosyltransferase using the STD NMR intensity-restrained CORCEMA optimization 2004
    2004 CORCEMA refinement of the bound ligand conformation within the protein binding pocket in reversibly forming weak complexes using STD-NMR intensities 2004
    2004 Saturation transfer difference NMR and computational modeling of a sialoadhesin-sialyl lactose complex 2004
    2002 Nitrolinoleate, a nitric oxide-derived mediator of cell function: Synthesis, characterization, and vasomotor activity 2002
    2002 Complete relaxation and conformational exchange matrix (CORCEMA) analysis of intermolecular saturation transfer effects in reversibly forming ligand-receptor complexes 2002
    2001 Solution structure of an insect-specific neurotoxin from the new world scorpion Centruroides sculpturatus Ewing 2001
    2001 Solution NMR structure of a model class A (apolipoprotein) amphipathic α helical peptide 2001
    2001 An economical method for 15N/13C isotopic labeling of proteins expressed in Pichia pastoris 2001
    2001 Automatic assignment of NOESY cross peaks and determination of the protein structure of a new world scorpion neurotoxin using NOAH/DIAMOD 2001
    2000 NMR solution structure of butantoxin 2000
    2000 Expression of functional recombinant scorpion β-neurotoxin Css II in E. coli 2000
    2000 Biochemical structural analysis of the lantibiotic mutacin II 2000
    2000 Structure of the coat protein-binding domain of the scaffolding protein from a double-stranded DNA virus 2000
    2000 De novo design of peptides targeted to the EF hands of calmodulin 2000
    1999 Synthesis and properties of some novel anti-calmodulin drugs 1999
    1999 Expression, purification, and characterization of interferon-τ produced in Pichia pastoris grown in a minimal medium 1999
    1999 NMR and molecular modeling studies on two glycopeptides from the carbohydrate-protein linkage region of connective tissue proteoglycans 1999
    1999 Solution structure of a β-neurotoxin from the New World scorpion Centruroides sculpturatus Ewing 1999
    1999 1H and 15N chemical shift assignments of a carboxy-terminal functional domain of the bacteriophage P22 scaffolding protein 1999
    1999 Nitration of unsaturated fatty acids by nitric oxide-derived reactive nitrogen species peroxynitrite, nitrous acid, nitrogen dioxide, and nitronium ion 1999
    1998 A helical coat protein recognition domain of the bacteriophage P22 scaffolding protein 1998
    1998 Solution Structure of the D/E Helix Linker of Skeletal Troponin-C: As Studied by Circular Dichroism and Two-Dimensional NMR Spectroscopy 1998
    1997 Analysis of the Morgan-Elson chromogens by high-performance liquid chromatography 1997
    1997 Structure and activity of the lantibiotic mutacin II. Evidence for two domains? 1997
    1997 The solution structure of a class II major histocompatibility complex superantigen binding domain 1997
    1997 Quantitative determination of conformational, dynamic, and kinetic parameters of a ligand-protein/DNA complex from a complete relaxation and conformational exchange matrix analysis of intermolecular transferred NOESY 1997
    1997 Cloning, purification, and preliminary characterization by circular dichroism and NMR of a carboxyl-terminal domain of the bacteriophage p22 scaffolding protein 1997
    1997 Partial purification and substrate specificity of heparan sulfate α-N-acetylglucosaminyltransferase I: Synthesis, NMR spectroscopic characterization and in vitro a assays of two aryl tetrasaccharides 1997
    1996 Complete 1H NMR assignments of synthetic glycopeptides from the carbohydrate-protein linkage region of serglycins 1996
    1996 Structural requirements for agonist activity of a murine interferon-γ peptide 1996
    1995 Complete Relaxation and Conformational Exchange Matrix (CORCEMA) Analysis of NOESY Spectra of Interacting Systems; Two-Dimensional Transferred NOESY 1995
    1995 A Global Optimization Method Based on Variable Target Functions for Fitting of the Experimental and Calculated NOESY Spectra 1995
    1995 A variable target intensity-restrained global optimization (VARTIGO) procedure for determining three-dimensional structures of polypeptides from NOESY data: Application to gramicidin-S 1995
    1995 Relative Effects of Protein-Mediated and Ligand-Mediated Spin-Diffusion Pathways on Transferred NOESY, and Implications on the Accuracy of the Bound Ligand Conformation 1995
    1995 Structure Determination from NOESY Intensities Using a Metropolis Simulated-Annealing (MSA) Refinement of Dihedral Angles 1995
    1994 Nuclear Magnetic Resonance Studies on Complementary Peptides 1994
    1994 A Vλx-bearing monoclonal antibody with similar specificity and sequence to encephalitogenic T cell receptors 1994
    1994 Proton Nuclear Magnetic Resonance and Distance Geometry/Simulated Annealing Studies on the Variant-1 Neurotoxin from the New World Scorpion Centruroides sculpturatus Ewing 1994
    1994 Predicted structural motif of ifnτ 1994
    1994 Solution structure of the variant‐3 neurotoxin from Centruroides sculpturatus Ewing 1994
    1993 Solution structure of trypsin modulating oostatic factor is a left-handed helix 1993
    1993 Proton NMR Sequence-Specific Assignments and Secondary Structure of a Receptor Binding Domain of Mouse γ-Interferon 1993
    1992 Influence of conformational exchange on the 2D NOESY spectra of biomolecules existing in multiple conformations 1992
    1992 Proton NMR study on rhamnolipids produced by Pseudomonas aeruginosa 1992
    1991 Structure of the type-specific polysaccharide antigen of Streptococcus rattus 1991
    1991 Characterization of cationic binding sites of neurotoxins from venom of the scorpion (Centruroides sculpturatus Ewing) using lanthanides as binding probes 1991
    1991 Effect of slow conformational exchange on 2D NOTEY spectra 1991
    1991 β‐Spiral conformations of the elastomeric polytetrapeptides, (VPGG)n and (IPGG)n, by 2D NMR and molecular mechanics studies 1991
    1990 Nuclear magnetic resonance and molecular modeling studies on O-β-D-galactopyranosyl-(1→4)-O-β-D-xylopyranosyl-(1→0)-L-serine, a carbohydrate-protein linkage region fragment from connective tissue proteoglycans 1990
    1990 NMR and fluorometric characterization of mithramycin in aqueous solution 1990
    1990 Synthesis of O-β-D-Galactopyranosyl-(1—>3)-O-β-D-Galactopyranosyl-(1->4)-0-β-D-Galactopyranosyl-(1—>3)—L—Serine (Gal-Gal-Xyl-Ser) 1990
    1989 Proton Nuclear Magnetic Resonance Characterization of the Aromatic Residues in the Variant-3 Neurotoxin from Centruroides sculpturatus Ewing 1989
    1989 Proton Nuclear Magnetic Resonance Studies on the Variant-3 Neurotoxin from Centruroides sculpturatus Ewing: Sequential Assignment of Resonances 1989
    1989 Proton nuclear magnetic resonance study of the biologically active peptide analog [Pro2]thymopentin 1989
    1989 Two‐dimensional proton NMR studies on poly(VPGVG) and its cyclic conformational correlate, cyclo(VPGVG)3 1989
    1988 1H NMR study of the solution structure of the self-complementary dodecanucleotide d(TGCA)3 1988
    1988 Structure of the group G Streptococcal polysaccharide 1988
    1987 Synthesis of 3-O-β-d-xylopyranosyl-l-serine (xylosylserine) and O-β-d-galactopyranosyl-(1-4)-O-β-d-xylopyranosyl-l-serine (galactosylxylosylserine) and use of the synthetic products for detection of galactosyltransferase I activity in rat liver 1987
    1987 Proton nuclear magnetic resonance measurement of the amide hydrogen exchange rates of group A streptococcal polysaccharide in H2O 1987
    1984 NMR study of in vivo RIF-1 tumors. Analysis of perchloric acid extracts and identification of 1H, 31P and 13C resonances 1984
    1983 13C nuclear magnetic resonance investigation of the Gd3+ complex of thymopentin 1983
    1983 Proton Nuclear Magnetic Resonance Investigation of the Active Site Fragment of Splenin, an Immunoregulatory Polypeptide 1983
    1982 Nuclear magnetic resonance analysis of Gd3+-induced perturbations in thymopoietin32-36: A study of amide and aromatic proton resonances 1982
    1982 Primary Amide Hydrogen Exchange in Model Amino Acids: Asparagine, Glutamine, and Glycine Amides 1982
    1981 Proton NMR investigation of Ln3+ complexes of thymopoietin32-36 1981
    1981 1H N.M.R. STUDY OF THE CONFORMATION OF [Glu 4] OXYTOCIN AND ITS LANTHANIDE COMPLEXES IN AQUEOUS SOLUTION 1981
    1981 Conformation of Angiotensin II. Evidence for a Specific Hydrogen Bonded Conformation 1981
    1981 Proton Nuclear Magnetic Resonance Study of an Active Pentapeptide Fragment of Ubiquitin 1981
    1981 Solution conformation of gramicidin S: An intramolecular nuclear Overhauser effect study 1981
    1980 A general multistate model for the analysis of hydrogen‐exchange kinetics 1980
    1980 Proton NMR study of iron(II)-bleomycin: Assignment of resonances by saturation transfer experiments 1980
    1980 Solution Conformation of Thymopoietin32-36: A Proton Nuclear Magnetic Resonance Study 1980
    1979 Amide hydrogen exchange rates of peptides in H2O solution by 1H nuclear magnetic resonance transfer of solvent saturation method. Conformations of oxytocin and lysine vasopressin in aqueous solution 1979
    1978 Conformational flexibility of bleomycin-A2: A carbon-13 spin-lattice relaxation time study 1978
    1978 Fourier transform double-resonance NMR on two- and three-spin systems 1978
    1978 Solution conformation of peptides by the intramolecular nuclear Overhauser effect experiment. Study of valinomycin-K+ 1978
    1976 A method for solvent peak suppression in FTNMR spectra by double resonance 1976
    1975 Fourier transform NMR in the rotating frame 1975
    1975 Proton spin relaxation in the halomethanes 1975
    1973 Intermolecular nuclear Overhauser effects in AnBnspin systems with asymmetric relaxation 1973
    1972 Fourier transform for a single nucleus of spin 1/2 in the presence of a strong rf field 1972
    1972 Relaxation effects in weakly-coupled three spin systems by double resonance 1972
    1971 Inter- and intramolecular dipole relaxation effects in double resonance spectra 1971
    1971 Proton cross relaxation effects in an AX2 system 1971
    1971 Proton spin relaxation in 2-chloroacrylonitrile by double resonance 1971
    1970 Intermolecular nuclear Overhauser effects in AnBnspin systems with asymmetric relaxation 1970

    Research Overview

  • My laboratory is primarily interested in biomolecular NMR spectroscopy, protein structural biology, and drug design. Recent work has centered around structure/function investigations and the characterization of motional dynamics in proteins and the development of computational methods and NMR methodologies for macromolecular structure refinement. Some of these investigations involve cross-disciplinary collaborative interactions with other research groups at UAB and elsewhere.

    Protein Structural Biology: Current work is aimed at understanding the structural biology of the capsid proteins of the HIV-1 virus and other retroviruses. The wild type capsid protein of HIV-1 is particularly challenging to study by 3D/4D-NMR because of its monomer-dimer equilibrium in solution and its tendency to form oligomers. It was also difficult to study by x-ray crycoverstallography because of its flexibility. Thus, we have utilized a double mutant of the HIV-1 CA (these mutations abolish its dimerization and infectivity, but preserve most of the properties of the wild type protein), and determined its detailed solution structure by 3D-NMR spectroscopy. The CTD domain in this full-length protein shows some differences from the previously published crystal and NMR structures of the wild type dimer structures. These differences give an insight about the mechanism of dimerization of the wild type protein. The structure of the monomeric mutant HIV-1

    CA will aid in the development of novel inhibitors that interfere with the HIV-1 life cycle at the level of assembly of the mature and immature capsids. It will also aid the development of inhibitors that interfere with the interaction of capsid protein with host cell proteins exploited by the virus in its replication cycle. We are also undertaking NMR structural studies to determine the role of calmodulin in Fas-mediated apoptosis of HIV-1 infected cells. A knowledge of the detailed three dimensional structures of calmodulin with cellular targets might lead to the development of calmodulin-antagonists that may have a therapeutic potential.

    Methodological Development: Our laboratory has an active interest in developing NMR-based structure-refinement procedures. In collaboration with Dr. Istvan Sugar at the Mt. Sinai Medical Center, New York, our laboratory has developed a variable target function based intensity-restrained global optimization procedure (VARTIGO) for refining the three-dimensional structures of proteins using NOESY data. We have developed an alternative method involving Metropolis Simulated Annealing (MSA) refinement of dihedral angles against experimental

    NOESY intensities. Another major project in our laboratory involved the development of a Complete Relaxation and Conformational Exchange Matrix (CORCEMA) procedure for interpreting the NOESY spectra of interacting molecules such as complexes of reversibly forming ligand-receptor complexes. The CORCEMA theory is very general and is applicable over a wide range of udp_gal_gtbdissociation constants for the complex (weak binding to tight binding). It incorporates explicitly all the pertinent protons of the interacting pair, and can account for the effect of motional dynamics in the complexes (e.g., hinge-bending motions in enzymes) on the NOESY. More recently, we have extended the CORCEMA theory to the saturation transfer difference (STD)-NMR experiment. This theory (CORCEMA-ST) is particularly useful in determining the bound conformations of reversibly binding low molecular weight lead compounds recognized by a target protein. Such information in turn can lead to structure-based design of new drugs. The CORCEMA-ST program is currently being utilized by over 82 different research groups including three major pharmaceutical companies in five different continents in their drug-design and developmental work. The CORCEMA and CORCEMA-ST programs may be obtained by contacting Dr. Krishna.

    This theory (CORCEMA-ST) is particularly useful in determining the bound conformations of reversibly binding low molecular weight lead compounds recognized by a target protein. Such information in turn can lead to structure-based design of new drugs. The CORCEMA-ST program is currently being utilized by over 75 research groups including three major pharmaceutical companies in five different continents in their drug-design and developmental work. The CORCEMA and CORCEMA-ST programs may be obtained by contacting Dr. Krishna.

    Central Alabama High-Field NMR Facility: With support from an NCRR High End Instrumentation Grant, NCI ARRA Supplement to the UAB Cancer Center, the UAB Administration (SOM, OVPRED, and CAS), the Cancer Center, and various Departments and Centers, we have established the Central Alabama High-Field NMR Facility equipped with a state-of-the-art 850 MHz NMR system (with a cryoprobe) as the center piece, along with several lower field NMR systems. This Facility will support the research programs of faculty members at UAB as well as at the neighboring institutions. This facility is located on the 1st floor of the UAB Department of Chemistry (14th street).
  • Full Name

  • N. Rama Krishna