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Attached is a program announcement that may be of interest.

PC6 at CU.NIH.GOV PC6 at CU.NIH.GOV
Wed Apr 5 17:01:06 EST 1995


STRUCTURAL BIOLOGY OF MEMBRANE PROTEINS

NIH GUIDE, Volume 24, Number 7, February 24, 1995

PA AVAILABLE:  PA-95-035

P.T. 34; K.W. 0760044, 0760070, 0790005, 0790015

National Institute of General Medical Sciences
National Institute of Diabetes and Digestive and Kidney Diseases

PURPOSE

The availability of the above program announcement (PA) is herein
announced.  The purpose of the PA is to encourage basic research on
the structures of membrane proteins at (or near) atomic resolution.
Considerable research is ongoing in the area of membrane protein
structure and function, particularly with respect to sequences,
topology, and the effects of mutations; however, much of this work is
somewhat speculative in that the interpretations depend upon the very
limited number of structures that have actually been solved by direct
biophysical measurements.  This program announcement is a
solicitation for the application of x-ray, electron, and neutron
diffraction methods, NMR spectroscopy, and other suitable techniques
to studies of membrane proteins.  It also emphasizes the need for
research on the over-expression, purification, reconstitution, and
stabilization of membrane proteins in sufficient quantities for
biophysical studies.  A major aim is to stimulate collaborations
between investigators with expertise in the handling of specific
membrane proteins and researchers with expertise in methods capable
of generating atomic resolution data.

INQUIRIES

The full text of the PA, which describes the research objectives,
application procedures, review considerations, and award criteria for
this program, may be obtained electronically through the NIH Grant
Line (data line (301) 402-2221) and the NIH GOPHER (gopher.nih.gov),
and by mail and email from the program contact listed below.

Peter C. Preusch, Ph.D.
Division of Pharmacology, Physiology, and Biological Chemistry
National Institute of General Medical Sciences
45 Center Drive, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-1832
FAX:  (301) 480-2802
Email:  PREUSCHP at gm1.nigms.nih.gov

Eliezar Dawidowicz, Ph.D.
Metabolism and Structural Biology Research Program
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, MSC 6600
Bethesda, MD  20892-6200
Telephone:  (301) 594-8811
FAX:  (301) 480-3503
Email:  LENNYD at dvsgate.niddk.nih.gov
STRUCTURAL BIOLOGY OF MEMBRANE PROTEINS

NIH GUIDE, Volume 24, Number 7, February 24, 1995

PA NUMBER:  PA-95-035

P.T. 34; K.W. 0760044, 0760070, 0790005, 0790015

National Institute of General Medical Sciences
National Institute of Diabetes and Digestive and Kidney Diseases

PURPOSE

The purpose of this program announcement (PA) is to encourage basic
research on the structures of membrane proteins at (or near) atomic
resolution.  Considerable research is on-going in the area of
membrane protein structure and function, particularly with respect to
sequences, topology, and the effects of mutations; however, much of
this work is somewhat speculative in that the interpretations depend
upon the very limited number of structures that have actually been
solved by direct biophysical measurements.  An increase in the number
of known membrane protein structures will contribute to an enhanced
understanding of many basic phenomena underlying cellular function.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by foreign and domestic, for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal government.
Foreign institutions are not eligible for First Independent Research
Support and Transition (FIRST) (R29) awards and program project (P01)
grants.  Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as principal investigators.

MECHANISM OF SUPPORT

Support of this program will be through the individual research
project grant (R01), program project grant (P01), and FIRST award
(R29).  Potential applicants are strongly urged to contact the
program staff listed under INQUIRIES for guidance in the areas
appropriate for program project grant applications and the
preparation of the application itself.

Investigators holding active R01, P01, or MERIT (R37) grants to study
membrane associated processes and who are not currently supported for
work on high resolution structural studies of the relevant membrane
associated proteins may wish to consider applying for competing
supplemental awards (S01).

RESEARCH OBJECTIVES

Membrane proteins play a crucial role in many cellular and
physiological processes.  They are essential mediators of material
and information transfer between cells and their environment, between
compartments within cells, and between compartments comprising the
organ systems.  Functionally normal membrane proteins are vital to
health and specific defects are associated with many known disease
states.  Membrane proteins are the targets of a large number of
pharmacologically and toxicologically active substances and are
responsible, in part, for their uptake, metabolism, and clearance.

Despite the importance of membrane associated proteins, the knowledge
of their high resolution structures and mechanisms of action has
lagged far behind the knowledge of these properties of proteins in
general.  This has resulted from the difficulty of obtaining x-ray
diffraction quality crystals for the membrane-embedded domains of
these proteins and the difficulty of applying well developed solution
NMR methods to the study of most membrane proteins.  These
difficulties have led to a reluctance of many investigators to pursue
high resolution structural studies.  However, in the recent past,
advances in methods for crystallization and analysis of proteins by
x-ray and electron diffraction methods, and improvements in NMR
methods, particularly solid-state NMR, have led to new opportunities.
The objective of this program announcement is two-fold:

1) To encourage investigators with interests in membrane associated
systems to pursue high resolution structural studies making use of
these recently developed technologies; and

2) To encourage additional research to further develop methods for
studying the structure of membrane proteins at atomic resolution.
Areas identified as needing specific attention include:

o  Improved methods for over-expression of native and modified
membrane proteins,

o  Improved methods for isolation, purification, and stabilization of
membrane proteins, including the development of new detergents and
non-detergent solubilization agents,

o  Basic research on the physical chemistry of membrane protein
crystallization and the development of new methods for
crystallization and crystal manipulation that could facilitate data
collection,

o  Further development of methods for electron diffraction,
particularly for the production of suitable 2D-crystals,

o  Further development of NMR methods for examining proteins in their
native lipid environments.

The techniques of x-ray or electron diffraction and of NMR
spectroscopy have been emphasized in this announcement, since it is
felt that they show the most promise for producing complete high
resolution information for the largest number of proteins.  However,
funds are also available for research using other methods that can
provide atomic resolution information in selected cases.  Methods
that can elucidate the organization of lipid and detergent molecules
within protein crystalline arrays (e.g., neutron diffraction) are
also of interest.

It is expected that many of the projects will be collaborative
efforts between biochemists and molecular biologists with expertise
in the isolation and characterization of membrane-bound proteins and
biophysicists with expertise in x-ray crystallography, NMR, and other
structural methods.  A major aim of this program announcement is to
stimulate such collaborations.

Membrane protein systems of particular interest to the National
Institute of General Medical Sciences (NIGMS) include:  energy
transducing membranes of mitochondria, chloroplasts, and bacterial
cell membranes involved in electron transport and ATP synthesis;
transporters of ions, substrates, and macromolecules between
intracellular compartments and between the cell and its environment;
enzymes in the synthesis and metabolism of lipids,
membrane-associated and secreted proteins, and glycoconjugates;
cytoskeletal proteins, including those required for intracellular
vesicle transport, cell motility, and cell division; regulators of
cell-cell communication, differentiation, and growth; receptors
relevant to cell cycle regulation, mechanisms of anesthetic action,
and trauma and burn physiology; transporters and enzymes responsible
for the uptake, metabolism, and clearance of drugs, or in other ways
affecting the bioavailability, pharmacokinetics, or action of drugs;
targets of drug action and toxicity, including targets of naturally
occurring toxins and venoms; enzymes involved in the biosynthesis of
natural products.

Membrane protein systems of particular interest to the National
Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
should have specific relevance to one of the following programmatic
areas: cystic fibrosis; carbohydrate metabolism and its hormonal
control; diabetes mellitus; hormone receptors and signal
transduction; endocrine disorders; normal and abnormal processes of
lipid, protein, amino acid, urea, pyrimidine, metal ion and steroid
metabolism; genetic metabolic disorders; diseases of peroxisomal
metabolism; diseases of transport; diseases of amino acid metabolism.
Proteins should be of mammalian origin.  Studies on proteins of
prokaryotic or lower eukaryotic origin should be proposed as models
for mammalian systems.  An example of this is the ABC transporter
superfamily or traffic ATPases in bacteria and yeast that serve as
models for the cystic fibrosis transmembrane regulator (CFTR).

The above listings are not meant to be exclusive.  Structural
information obtained for any membrane protein will contribute to
understanding the general principles that underlie all membrane
protein structure and function.  Research on the non-membrane
embedded proteins associated with many of the cellular functions
listed above is also supported by NIGMS and NIDDK; however, this
program announcement is intended to emphasize the need for additional
research on structural aspects of the membrane-embedded proteins
involved in these processes.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS
398 (rev. 9/91) and will be accepted at the standard application



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