Proteopedia - User contributions [en]

Dihydrofolate reductase

2008-01-22T20:32:45Z

Tzvia Selzer:

[[Image:1rx2.jpg|left|150px]] 
<applet load='1rx2' size='300' color='white' frame='true' spin='on' caption='DHFR' align='right' />
'''3D structure of dihydrofolate reductase''' 
== The sole source of tetrahydrofolate==

DHFR is a ubiquitous enzyme found in all organisms. The primary physiological role of DHFR is maintenance of the intracellular levels of tetrahydrofolate, a precursor of cofactors required for the biosynthesis of purines, pyrimidines, and several amino acids.

The enzyme, which is the sole source of tetrahydrofolate catalyzes the reduction of <scene name='Dihydrofolate_reductase/Dihydrofolate/1'>7,8-dihydrofolate</scene> (DHF) to 5,6,7,8-tetrahydrofolate (THF) by stereospecific hydride transfer from the <scene name='Dihydrofolate_reductase/Nadph/2'>NADPH</scene> cofactor to the C6 atom of the pterin ring with concomitant protonation at N5.
Being the sole source of THF it is an Achilles’ heel of rapidly proliferating cells, making it an attractive target of several important anticancer and antimicrobial drugs such as methotrexate, trimethoprim, and pyrimethamine.

E. coli DHFR is a small (18 kD) protein with an a/b structure consisting of a central eight-stranded b-sheet and four flanking a helices. The active site cleft divides the protein into two structural subdomains: the <scene name='Dihydrofolate_reductase/Adenosine_sub/2'>Adenosine binding subdomain</scene> (red) and the <scene name='Dihydrofolate_reductase/Adenosine_sub/3'>major subdomain</scene> (green). The adenosine binding subdomain is the smaller of the two subdomains and provides the binding site for the adenosine moiety of the cofactor. The major subdomain consists of ~100 residues from the N and C termini and is dominated by a set of three loops on the ligand binding face that surround the active site. In terms of sequence length, these loops make up approximately 40%–50% of the major subdomain; hence it is sometimes called the “loop” subdomain. The loops are termed Met20, F-G, and G-H loops. Hinge bending motions about Lys38 and Val88 allow the adenosine binding domain to move relative to the major domain upon binding of various ligands, resulting in closure of the active site cleft.

[[Image:Met20loop.png|left|250px]] 

A movie depicting the conformational changes of DHFR during one turnover of substrate has been constructed by M. R. Sawaya and J. Kraut using six isomorphous crystallographic structures.
http://chem-faculty.ucsd.edu/kraut/dhfr.html

Dihydrofolate reductase

2008-01-22T20:32:05Z

Tzvia Selzer:

[[Image:1rx2.jpg|left|150px]] 
<applet load='1rx2' size='300' color='white' frame='true' spin='on' caption='DHFR' align='right' />
'''3D structure of dihydrofolate reductase''' 
== The sole source of tetrahydrofolate==

DHFR is a ubiquitous enzyme found in all organisms. The primary physiological role of DHFR is maintenance of the intracellular levels of tetrahydrofolate, a precursor of cofactors required for the biosynthesis of purines, pyrimidines, and several amino acids.

The enzyme, which is the sole source of tetrahydrofolate catalyzes the reduction of <scene name='Dihydrofolate_reductase/Dihydrofolate/1'>7,8-dihydrofolate</scene> (DHF) to 5,6,7,8-tetrahydrofolate (THF) by stereospecific hydride transfer from the <scene name='Dihydrofolate_reductase/Nadph/2'>NADPH</scene> cofactor to the C6 atom of the pterin ring with concomitant protonation at N5.
Being the sole source of THF it is an Achilles’ heel of rapidly proliferating cells, making it an attractive target of several important anticancer and antimicrobial drugs such as methotrexate, trimethoprim, and pyrimethamine.

E. coli DHFR is a small (18 kD) protein with an a/b structure consisting of a central eight-stranded b-sheet and four flanking a helices. The active site cleft divides the protein into two structural subdomains: the <scene name='Dihydrofolate_reductase/Adenosine_sub/2'>Adenosine binding subdomain</scene> (red) and the <scene name='Dihydrofolate_reductase/Adenosine_sub/3'>major subdomain</scene> (green). The adenosine binding subdomain is the smaller of the two subdomains and provides the binding site for the adenosine moiety of the cofactor. The major subdomain consists of ~100 residues from the N and C termini and is dominated by a set of three loops on the ligand binding face that surround the active site. In terms of sequence length, these loops make up approximately 40%–50% of the major subdomain; hence it is sometimes called the “loop” subdomain. The loops are termed Met20, F-G, and G-H loops. Hinge bending motions about Lys38 and Val88 allow the adenosine binding domain to move relative to the major domain upon binding of various ligands, resulting in closure of the active site cleft.

[[Image:Met20loop.png|left|150px]] 

A movie depicting the conformational changes of DHFR during one turnover of substrate has been constructed by M. R. Sawaya and J. Kraut using six isomorphous crystallographic structures.
http://chem-faculty.ucsd.edu/kraut/dhfr.html

Matrix metalloproteinases

2008-01-22T13:15:06Z

Tzvia Selzer:

[[Image:2clt_bio_r_250.jpg|left|150px]] 
<applet load='2clt' size='300' color='white' frame='true' spin='on' caption='MMP' align='right' />
'''3D structure of matrix metalloproteinases''' 
== Endopeptidases involved in the degradation of the extracellular matrix==

The matrix metalloproteinases (MMPs) are zinc- and calcium dependent neutral endopeptidases involved in the degradation of the extracellular matrix and in tissue remodeling. Currently, approximately 27 MMPs are known. These have been grouped into subfamilies on the basis of their substrate specificity. Transcriptional regulation, zymogen activation and endogenous inhibitors control MMP activity under normal physiological conditions. Disturbance of this physiological balance may lead to an overexpression of MMPs followed by accelerated matrix degradation. The latter is associated with several pathologies including cancer cell invasion and metastasis, the loss of cartilage in osteoarthritis, rheumatoid arthritis, cardiovascular diseases, acute lung injury, chronic obstructive pulmonary disease, eye and skin diseases and periodontitis. As a consequence, the MMP family has emerged as an attractive pharmaceutical target.
Blocking MMP gene transcription, proenzyme activation or active site-directed inhibitions are possible approaches for therapeutic intervention.

Matrix metalloproteinases

2008-01-22T13:14:01Z

Tzvia Selzer:

[[Image:2clt-bio-r-250.jpg|left|150px]] 
<applet load='2clt_bio_r_250' size='300' color='white' frame='true' spin='on' caption='MMP' align='right' />
'''3D structure of matrix metalloproteinases''' 
== Endopeptidases involved in the degradation of the extracellular matrix==

The matrix metalloproteinases (MMPs) are zinc- and calcium dependent neutral endopeptidases involved in the degradation of the extracellular matrix and in tissue remodeling. Currently, approximately 27 MMPs are known. These have been grouped into subfamilies on the basis of their substrate specificity. Transcriptional regulation, zymogen activation and endogenous inhibitors control MMP activity under normal physiological conditions. Disturbance of this physiological balance may lead to an overexpression of MMPs followed by accelerated matrix degradation. The latter is associated with several pathologies including cancer cell invasion and metastasis, the loss of cartilage in osteoarthritis, rheumatoid arthritis, cardiovascular diseases, acute lung injury, chronic obstructive pulmonary disease, eye and skin diseases and periodontitis. As a consequence, the MMP family has emerged as an attractive pharmaceutical target.
Blocking MMP gene transcription, proenzyme activation or active site-directed inhibitions are possible approaches for therapeutic intervention.

Matrix metalloproteinases

2008-01-22T13:13:28Z

Tzvia Selzer:

[[Image:2clt_bio_r_250.jpg|left|150px]] 
<applet load='2clt_bio_r_250' size='300' color='white' frame='true' spin='on' caption='MMP' align='right' />
'''3D structure of matrix metalloproteinases''' 
== Endopeptidases involved in the degradation of the extracellular matrix==

The matrix metalloproteinases (MMPs) are zinc- and calcium dependent neutral endopeptidases involved in the degradation of the extracellular matrix and in tissue remodeling. Currently, approximately 27 MMPs are known. These have been grouped into subfamilies on the basis of their substrate specificity. Transcriptional regulation, zymogen activation and endogenous inhibitors control MMP activity under normal physiological conditions. Disturbance of this physiological balance may lead to an overexpression of MMPs followed by accelerated matrix degradation. The latter is associated with several pathologies including cancer cell invasion and metastasis, the loss of cartilage in osteoarthritis, rheumatoid arthritis, cardiovascular diseases, acute lung injury, chronic obstructive pulmonary disease, eye and skin diseases and periodontitis. As a consequence, the MMP family has emerged as an attractive pharmaceutical target.
Blocking MMP gene transcription, proenzyme activation or active site-directed inhibitions are possible approaches for therapeutic intervention.

Matrix metalloproteinases

2008-01-22T13:12:22Z

Tzvia Selzer:

Matrix metalloproteinases

2008-01-22T13:00:45Z

Tzvia Selzer:

[[Image:2clt.jpg|left|150px]] 
<applet load='2clt' size='300' color='white' frame='true' spin='on' caption='MMP' align='right' />
'''3D structure of matrix metalloproteinases''' 
== Endopeptidases involved in the degradation of the extracellular matrix==

The matrix metalloproteinases (MMPs) are zinc- and calcium dependent neutral endopeptidases involved in the degradation of the extracellular matrix and in tissue remodeling. Currently, approximately 27 MMPs are known. These have been grouped into subfamilies on the basis of their substrate specificity. Transcriptional regulation, zymogen activation and endogenous inhibitors control MMP activity under normal physiological conditions. Disturbance of this physiological balance may lead to an overexpression of MMPs followed by accelerated matrix degradation. The latter is associated with several pathologies including cancer cell invasion and metastasis, the loss of cartilage in osteoarthritis, rheumatoid arthritis, cardiovascular diseases, acute lung injury, chronic obstructive pulmonary disease, eye and skin diseases and periodontitis. As a consequence, the MMP family has emerged as an attractive pharmaceutical target.
Blocking MMP gene transcription, proenzyme activation or active site-directed inhibitions are possible approaches for therapeutic intervention.

Matrix metalloproteinases

2008-01-22T12:59:56Z

Tzvia Selzer:

[[Image:2clt.jpg|left|150px]] 
<applet load='2clt:a' size='300' color='white' frame='true' spin='on' caption='MMP' align='right' />
'''3D structure of matrix metalloproteinases''' 
== Endopeptidases involved in the degradation of the extracellular matrix==

The matrix metalloproteinases (MMPs) are zinc- and calcium dependent neutral endopeptidases involved in the degradation of the extracellular matrix and in tissue remodeling. Currently, approximately 27 MMPs are known. These have been grouped into subfamilies on the basis of their substrate specificity. Transcriptional regulation, zymogen activation and endogenous inhibitors control MMP activity under normal physiological conditions. Disturbance of this physiological balance may lead to an overexpression of MMPs followed by accelerated matrix degradation. The latter is associated with several pathologies including cancer cell invasion and metastasis, the loss of cartilage in osteoarthritis, rheumatoid arthritis, cardiovascular diseases, acute lung injury, chronic obstructive pulmonary disease, eye and skin diseases and periodontitis. As a consequence, the MMP family has emerged as an attractive pharmaceutical target.
Blocking MMP gene transcription, proenzyme activation or active site-directed inhibitions are possible approaches for therapeutic intervention.

Matrix metalloproteinases

2008-01-22T12:37:19Z

Tzvia Selzer: New page: 150px <applet load='2clt' size='300' color='white' frame='true' spin='on' caption='MMP' align='right' /> '''3D structure of matrix metalloproteinases''' ...

Dihydrofolate reductase

2008-01-20T14:27:49Z

Tzvia Selzer:

[[Image:1rx2.jpg|left|150px]] 
<applet load='1rx2' size='300' color='white' frame='true' spin='on' caption='DHFR' align='right' />
'''3D structure of dihydrofolate reductase''' 
== The sole source of tetrahydrofolate==

DHFR is a ubiquitous enzyme found in all organisms. The primary physiological role of DHFR is maintenance of the intracellular levels of tetrahydrofolate, a precursor of cofactors required for the biosynthesis of purines, pyrimidines, and several amino acids.

The enzyme, which is the sole source of tetrahydrofolate catalyzes the reduction of <scene name='Dihydrofolate_reductase/Dihydrofolate/1'>7,8-dihydrofolate</scene> (DHF) to 5,6,7,8-tetrahydrofolate (THF) by stereospecific hydride transfer from the <scene name='Dihydrofolate_reductase/Nadph/2'>NADPH</scene> cofactor to the C6 atom of the pterin ring with concomitant protonation at N5.
Being the sole source of THF it is an Achilles’ heel of rapidly proliferating cells, making it an attractive target of several important anticancer and antimicrobial drugs such as methotrexate, trimethoprim, and pyrimethamine.

E. coli DHFR is a small (18 kD) protein with an a/b structure consisting of a central eight-stranded b-sheet and four flanking a helices. The active site cleft divides the protein into two structural subdomains: the <scene name='Dihydrofolate_reductase/Adenosine_sub/2'>Adenosine binding subdomain</scene> (red) and the <scene name='Dihydrofolate_reductase/Adenosine_sub/3'>major subdomain</scene> (green). The adenosine binding subdomain is the smaller of the two subdomains and provides the binding site for the adenosine moiety of the cofactor. The major subdomain consists of ~100 residues from the N and C termini and is dominated by a set of three loops on the ligand binding face that surround the active site. In terms of sequence length, these loops make up approximately 40%–50% of the major subdomain; hence it is sometimes called the “loop” subdomain. The loops are termed Met20, F-G, and G-H loops. Hinge bending motions about Lys38 and Val88 allow the adenosine binding domain to move relative to the major domain upon binding of various ligands, resulting in closure of the active site cleft.

A movie depicting the conformational changes of DHFR during one turnover of substrate has been constructed by M. R. Sawaya and J. Kraut using six isomorphous crystallographic structures.
http://chem-faculty.ucsd.edu/kraut/dhfr.html

Dihydrofolate reductase

2008-01-20T14:26:21Z

Tzvia Selzer:

[[Image:1rx2.jpg|left|150px]] 
<applet load='1rx2' size='300' color='white' frame='true' spin='on' caption='DHFR' align='right' />
'''3D structure of dihydrofolate reductase''' 
== The sole source of tetrahydrofolate==

DHFR is a ubiquitous enzyme found in all organisms. The primary physiological role of DHFR is maintenance of the intracellular levels of tetrahydrofolate, a precursor of cofactors required for the biosynthesis of purines, pyrimidines, and several amino acids.

The enzyme, which is the sole source of tetrahydrofolate catalyzes the reduction of <scene name='Dihydrofolate_reductase/Dihydrofolate/1'>7,8-dihydrofolate</scene> (DHF) to 5,6,7,8-tetrahydrofolate (THF) by stereospecific hydride transfer from the <scene name='Dihydrofolate_reductase/Nadph/2'>NADPH</scene> cofactor to the C6 atom of the pterin ring with concomitant protonation at N5.
Being the sole source of THF it is an Achilles’ heel of rapidly proliferating cells, making it an attractive target of several important anticancer and antimicrobial drugs such as methotrexate, trimethoprim, and pyrimethamine.

E. coli DHFR is a small (18 kD) protein with an a/b structure consisting of a central eight-stranded b-sheet and four flanking a helices. The active site cleft divides the protein into two structural subdomains: the <scene name='Dihydrofolate_reductase/Adenosine_sub/2'>Adenosine binding subdomain</scene> and the <scene name='Dihydrofolate_reductase/Adenosine_sub/3'>major subdomain</scene>. The adenosine binding subdomain is the smaller of the two subdomains and provides the binding site for the adenosine moiety of the cofactor. The major subdomain consists of ~100 residues from the N and C termini and is dominated by a set of three loops on the ligand binding face that surround the active site. In terms of sequence length, these loops make up approximately 40%–50% of the major subdomain; hence it is sometimes called the “loop” subdomain. The loops are termed Met20, F-G, and G-H loops. Hinge bending motions about Lys38 and Val88 allow the adenosine binding domain to move relative to the major domain upon binding of various ligands, resulting in closure of the active site cleft.

A movie depicting the conformational changes of DHFR during one turnover of substrate has been constructed by M. R. Sawaya and J. Kraut using six isomorphous crystallographic structures.
http://chem-faculty.ucsd.edu/kraut/dhfr.html

Dihydrofolate reductase

2008-01-20T14:14:11Z

Tzvia Selzer:

[[Image:1rx2.jpg|left|150px]] 
<applet load='1rx2' size='300' color='white' frame='true' spin='on' caption='DHFR' align='right' />
'''3D structure of dihydrofolate reductase''' 
== The sole source of tetrahydrofolate==

DHFR is a ubiquitous enzyme found in all organisms. The primary physiological role of DHFR is maintenance of the intracellular levels of tetrahydrofolate, a precursor of cofactors required for the biosynthesis of purines, pyrimidines, and several amino acids.

The enzyme, which is the sole source of tetrahydrofolate catalyzes the reduction of <scene name='Dihydrofolate_reductase/Dihydrofolate/1'>7,8-dihydrofolate</scene> (DHF) to 5,6,7,8-tetrahydrofolate (THF) by stereospecific hydride transfer from the <scene name='Dihydrofolate_reductase/Nadph/2'>NADPH</scene> cofactor to the C6 atom of the pterin ring with concomitant protonation at N5.
Being the sole source of THF it is an Achilles’ heel of rapidly proliferating cells, making it an attractive target of several important anticancer and antimicrobial drugs such as methotrexate, trimethoprim, and pyrimethamine.

E. coli DHFR is a small (18 kD) protein with an a/b structure consisting of a central eight-stranded b-sheet and four flanking a helices. The active site cleft divides the protein into two structural subdomains: the <scene name='Dihydrofolate_reductase/Adenosine_sub/1'>adenosine binding subdomain</scene> and the major subdomain. The adenosine binding subdomain is the smaller of the two subdomains and provides the binding site for the adenosine moiety of the cofactor. The major subdomain consists of ~100 residues from the N and C termini and is dominated by a set of three loops on the ligand binding face that surround the active site. In terms of sequence length, these loops make up approximately 40%–50% of the major subdomain; hence it is sometimes called the “loop” subdomain. The loops are termed Met20, F-G, and G-H loops. Hinge bending motions about Lys38 and Val88 allow the adenosine binding domain to move relative to the major domain upon binding of various ligands, resulting in closure of the active site cleft.

A movie depicting the conformational changes of DHFR during one turnover of substrate has been constructed by M. R. Sawaya and J. Kraut using six isomorphous crystallographic structures.
http://chem-faculty.ucsd.edu/kraut/dhfr.html

Dihydrofolate reductase

2008-01-20T14:03:52Z

Tzvia Selzer:

[[Image:1rx2.jpg|left|150px]] 
<applet load='1rx2' size='300' color='white' frame='true' spin='on' caption='DHFR' align='right' />
'''3D structure of dihydrofolate reductase''' 
== The sole source of tetrahydrofolate==

DHFR is a ubiquitous enzyme found in all organisms. The primary physiological role of DHFR is maintenance of the intracellular levels of tetrahydrofolate, a precursor of cofactors required for the biosynthesis of purines, pyrimidines, and several amino acids.

The enzyme, which is the sole source of tetrahydrofolate catalyzes the reduction of <scene name='Dihydrofolate_reductase/Dihydrofolate/1'>7,8-dihydrofolate</scene> (DHF) to 5,6,7,8-tetrahydrofolate (THF) by stereospecific hydride transfer from the <scene name='Dihydrofolate_reductase/Nadph/1'>NADPH</scene> cofactor to the C6 atom of the pterin ring with concomitant protonation at N5.
Being the sole source of THF it is an Achilles’ heel of rapidly proliferating cells, making it an attractive target of several important anticancer and antimicrobial drugs such as methotrexate, trimethoprim, and pyrimethamine.

E. coli DHFR is a small (18 kD) protein with an a/b structure consisting of a central eight-stranded b-sheet and four flanking a helices. The active site cleft divides the protein into two structural subdomains: the <scene name='Dihydrofolate_reductase/Adenosine_sub/1'>adenosine binding subdomain</scene> and the major subdomain. The adenosine binding subdomain is the smaller of the two subdomains and provides the binding site for the adenosine moiety of the cofactor. The major subdomain consists of ~100 residues from the N and C termini and is dominated by a set of three loops on the ligand binding face that surround the active site. In terms of sequence length, these loops make up approximately 40%–50% of the major subdomain; hence it is sometimes called the “loop” subdomain. The loops are termed Met20, F-G, and G-H loops. Hinge bending motions about Lys38 and Val88 allow the adenosine binding domain to move relative to the major domain upon binding of various ligands, resulting in closure of the active site cleft.

A movie depicting the conformational changes of DHFR during one turnover of substrate has been constructed by M. R. Sawaya and J. Kraut using six isomorphous crystallographic structures.
http://chem-faculty.ucsd.edu/kraut/dhfr.html

Dihydrofolate reductase

2008-01-17T09:41:02Z

Tzvia Selzer:

[[Image:1rx2.jpg|left|150px]] 
<applet load='1rx2' size='300' color='white' frame='true' spin='on' caption='DHFR' align='right' />
'''3D structure of dihydrofolate reductase''' 
== The sole source of tetrahydrofolate==

DHFR is a ubiquitous enzyme found in all organisms. The primary physiological role of DHFR is maintenance of the intracellular levels of tetrahydrofolate, a precursor of cofactors required for the biosynthesis of purines, pyrimidines, and several amino acids.

The enzyme, which is the sole source of tetrahydrofolate catalyzes the reduction of <scene name='Dihydrofolate_reductase/Dihydrofolate/1'>7,8-dihydrofolate</scene> (DHF) to 5,6,7,8-tetrahydrofolate (THF) by stereospecific hydride transfer from the <scene name='Dihydrofolate_reductase/Nadph/1'>NADPH</scene> cofactor to the C6 atom of the pterin ring with concomitant protonation at N5.
Being the sole source of THF it is an Achilles’ heel of rapidly proliferating cells, making it an attractive target of several important anticancer and antimicrobial drugs such as methotrexate, trimethoprim, and pyrimethamine.

E. coli DHFR is a small (18 kD) protein with an a/b structure consisting of a central eight-stranded b-sheet and four flanking a helices. The active site cleft divides the protein into two structural subdomains: the adenosine binding subdomain and the major subdomain. The adenosine binding subdomain is the smaller of the two subdomains and provides the binding site for the adenosine moiety of the cofactor. The major subdomain consists of ~100 residues from the N and C termini and is dominated by a set of three loops on the ligand binding face that surround the active site. In terms of sequence length, these loops make up approximately 40%–50% of the major subdomain; hence it is sometimes called the “loop” subdomain. The loops are termed Met20, F-G, and G-H loops. Hinge bending motions about Lys38 and Val88 allow the adenosine binding domain to move relative to the major domain upon binding of various ligands, resulting in closure of the active site cleft.

A movie depicting the conformational changes of DHFR during one turnover of substrate has been constructed by M. R. Sawaya and J. Kraut using six isomorphous crystallographic structures.
http://chem-faculty.ucsd.edu/kraut/dhfr.html

Dihydrofolate reductase

2008-01-17T09:32:33Z

Tzvia Selzer:

[[Image:1rx2.jpg|left|150px]] 
<applet load='1rx2' size='300' color='white' frame='true' spin='on' caption='DHFR' align='right' />
'''3D structure of dihydrofolate reductase''' 
== The sole source of tetrahydrofolate==

DHFR is a ubiquitous enzyme found in all organisms. The primary physiological role of DHFR is maintenance of the intracellular levels of tetrahydrofolate, a precursor of cofactors required for the biosynthesis of purines, pyrimidines, and several amino acids.

The enzyme, which is the sole source of tetrahydrofolate catalyzes the reduction of <scene name='Dihydrofolate_reductase/Dihydrofolate/1'>7,8-dihydrofolate</scene> (DHF) to 5,6,7,8-tetrahydrofolate (THF) by stereospecific hydride transfer from the NADPH cofactor to the C6 atom of the pterin ring with concomitant protonation at N5.
Being the sole source of THF it is an Achilles’ heel of rapidly proliferating cells, making it an attractive target of several important anticancer and antimicrobial drugs such as methotrexate, trimethoprim, and pyrimethamine.

E. coli DHFR is a small (18 kD) protein with an a/b structure consisting of a central eight-stranded b-sheet and four flanking a helices. The active site cleft divides the protein into two structural subdomains: the adenosine binding subdomain and the major subdomain. The adenosine binding subdomain is the smaller of the two subdomains and provides the binding site for the adenosine moiety of the cofactor. The major subdomain consists of ~100 residues from the N and C termini and is dominated by a set of three loops on the ligand binding face that surround the active site. In terms of sequence length, these loops make up approximately 40%–50% of the major subdomain; hence it is sometimes called the “loop” subdomain. The loops are termed Met20, F-G, and G-H loops. Hinge bending motions about Lys38 and Val88 allow the adenosine binding domain to move relative to the major domain upon binding of various ligands, resulting in closure of the active site cleft.

A movie depicting the conformational changes of DHFR during one turnover of substrate has been constructed by M. R. Sawaya and J. Kraut using six isomorphous crystallographic structures.
http://chem-faculty.ucsd.edu/kraut/dhfr.html

Dihydrofolate reductase

2008-01-17T08:26:58Z

Tzvia Selzer:

[[Image:1rx2.jpg|left|150px]] 
<applet load='1rx2' size='300' color='white' frame='true' spin='on' caption='DHFR' align='right' />
'''3D structure of dihydrofolate reductase''' 
== The sole source of tetrahydrofolate==

DHFR is a ubiquitous enzyme found in all organisms. The primary physiological role of DHFR is maintenance of the intracellular levels of tetrahydrofolate, a precursor of cofactors required for the biosynthesis of purines, pyrimidines, and several amino acids.

The enzyme, which is the sole source of tetrahydrofolate catalyzes the reduction of 7,8-dihydrofolate (DHF) to 5,6,7,8-tetrahydrofolate (THF) by stereospecific hydride transfer from the NADPH cofactor to the C6 atom of the pterin ring with concomitant protonation at N5.
Being the sole source of THF it is an Achilles’ heel of rapidly proliferating cells, making it an attractive target of several important anticancer and antimicrobial drugs such as methotrexate, trimethoprim, and pyrimethamine.

E. coli DHFR is a small (18 kD) protein with an a/b structure consisting of a central eight-stranded b-sheet and four flanking a helices. The active site cleft divides the protein into two structural subdomains: the adenosine binding subdomain and the major subdomain. The adenosine binding subdomain is the smaller of the two subdomains and provides the binding site for the adenosine moiety of the cofactor. The major subdomain consists of ~100 residues from the N and C termini and is dominated by a set of three loops on the ligand binding face that surround the active site. In terms of sequence length, these loops make up approximately 40%–50% of the major subdomain; hence it is sometimes called the “loop” subdomain. The loops are termed Met20, F-G, and G-H loops. Hinge bending motions about Lys38 and Val88 allow the adenosine binding domain to move relative to the major domain upon binding of various ligands, resulting in closure of the active site cleft.

A movie depicting the conformational changes of DHFR during one turnover of substrate has been constructed by M. R. Sawaya and J. Kraut using six isomorphous crystallographic structures.
http://chem-faculty.ucsd.edu/kraut/dhfr.html

Dihydrofolate reductase

2008-01-17T08:26:23Z

Tzvia Selzer:

[[Image:1rx2.jpg|left|150px]] 
<applet load='1rx2' size='300' color='white' frame='true' spin='on' caption='DHFR' align='right' />
'''3D structure of dihydrofolate reductase''' 
== The sole source of tetrahydrofolate==

DHFR is a ubiquitous enzyme found in all organisms. The primary physiological role of DHFR is maintenance of the intracellular levels of tetrahydrofolate, a precursor of cofactors required for the biosynthesis of purines, pyrimidines, and several amino acids.

The enzyme, which is the sole source of tetrahydrofolate catalyzes the reduction of 7,8-dihydrofolate (DHF) to 5,6,7,8-tetrahydrofolate (THF) by stereospecific hydride transfer from the [[NADPH]] cofactor to the C6 atom of the pterin ring with concomitant protonation at N5.
Being the sole source of THF it is an Achilles’ heel of rapidly proliferating cells, making it an attractive target of several important anticancer and antimicrobial drugs such as methotrexate, trimethoprim, and pyrimethamine.

E. coli DHFR is a small (18 kD) protein with an a/b structure consisting of a central eight-stranded b-sheet and four flanking a helices. The active site cleft divides the protein into two structural subdomains: the adenosine binding subdomain and the major subdomain. The adenosine binding subdomain is the smaller of the two subdomains and provides the binding site for the adenosine moiety of the cofactor. The major subdomain consists of ~100 residues from the N and C termini and is dominated by a set of three loops on the ligand binding face that surround the active site. In terms of sequence length, these loops make up approximately 40%–50% of the major subdomain; hence it is sometimes called the “loop” subdomain. The loops are termed Met20, F-G, and G-H loops. Hinge bending motions about Lys38 and Val88 allow the adenosine binding domain to move relative to the major domain upon binding of various ligands, resulting in closure of the active site cleft.

A movie depicting the conformational changes of DHFR during one turnover of substrate has been constructed by M. R. Sawaya and J. Kraut using six isomorphous crystallographic structures.
http://chem-faculty.ucsd.edu/kraut/dhfr.html

Dihydrofolate reductase

2008-01-16T14:04:22Z

Tzvia Selzer:

[[Image:1rx2.jpg|left|150px]] 
<applet load='1rx2' size='300' color='white' frame='true' spin='on' caption='DHFR' align='right' script='Dihydrofolate reductase'
'''3D structure of dihydrofolate reductase''' 
== The sole source of tetrahydrofolate==

DHFR is a ubiquitous enzyme found in all organisms. The primary physiological role of DHFR is maintenance of the intracellular levels of tetrahydrofolate, a precursor of cofactors required for the biosynthesis of purines, pyrimidines, and several amino acids.

The enzyme, which is the sole source of tetrahydrofolate catalyzes the reduction of 7,8-dihydrofolate (DHF) to 5,6,7,8-tetrahydrofolate (THF) by stereospecific hydride transfer from the NADPH cofactor to the C6 atom of the pterin ring with concomitant protonation at N5.
Being the sole source of THF it is an Achilles’ heel of rapidly proliferating cells, making it an attractive target of several important anticancer and antimicrobial drugs such as methotrexate, trimethoprim, and pyrimethamine.

E. coli DHFR is a small (18 kD) protein with an a/b structure consisting of a central eight-stranded b-sheet and four flanking a helices. The active site cleft divides the protein into two structural subdomains: the adenosine binding subdomain and the major subdomain. The adenosine binding subdomain is the smaller of the two subdomains and provides the binding site for the adenosine moiety of the cofactor. The major subdomain consists of ~100 residues from the N and C termini and is dominated by a set of three loops on the ligand binding face that surround the active site. In terms of sequence length, these loops make up approximately 40%–50% of the major subdomain; hence it is sometimes called the “loop” subdomain. The loops are termed Met20, F-G, and G-H loops. Hinge bending motions about Lys38 and Val88 allow the adenosine binding domain to move relative to the major domain upon binding of various ligands, resulting in closure of the active site cleft.

Dihydrofolate reductase

2008-01-16T13:57:23Z

Tzvia Selzer:

Dihydrofolate reductase

2008-01-16T13:56:50Z

Tzvia Selzer:

[[Image:1rx2.jpg|left|150px]] 
<applet load='1RX2.pdb' size='300' color='white' frame='true' spin='on' caption='DHFR' align='right' script='Dihydrofolate reductase'
'''3D structure of dihydrofolate reductase''' 
== The sole source of tetrahydrofolate==

DHFR is a ubiquitous enzyme found in all organisms. The primary physiological role of DHFR is maintenance of the intracellular levels of tetrahydrofolate, a precursor of cofactors required for the biosynthesis of purines, pyrimidines, and several amino acids.

The enzyme, which is the sole source of tetrahydrofolate catalyzes the reduction of 7,8-dihydrofolate (DHF) to 5,6,7,8-tetrahydrofolate (THF) by stereospecific hydride transfer from the NADPH cofactor to the C6 atom of the pterin ring with concomitant protonation at N5.
Being the sole source of THF it is an Achilles’ heel of rapidly proliferating cells, making it an attractive target of several important anticancer and antimicrobial drugs such as methotrexate, trimethoprim, and pyrimethamine.

Dihydrofolate reductase

2008-01-16T13:42:36Z

Tzvia Selzer:

[[Image:.jpg|left|150px]] 
<applet load='1RX2.pdb' size='300' color='white' frame='true' spin='on' caption='DHFR' align='right' script='Dihydrofolate reductase'
'''3D structure of dihydrofolate reductase''' 
== The sole source of tetrahydrofolate==

DHFR is a ubiquitous enzyme found in all organisms. The primary physiological role of DHFR is maintenance of the intracellular levels of tetrahydrofolate, a precursor of cofactors required for the biosynthesis of purines, pyrimidines, and several amino acids.

The enzyme, which is the sole source of tetrahydrofolate catalyzes the reduction of 7,8-dihydrofolate (DHF) to 5,6,7,8-tetrahydrofolate (THF) by stereospecific hydride transfer from the NADPH cofactor to the C6 atom of the pterin ring with concomitant protonation at N5.
Being the sole source of THF it is an Achilles’ heel of rapidly proliferating cells, making it an attractive target of several important anticancer and antimicrobial drugs such as methotrexate, trimethoprim, and pyrimethamine.

Dihydrofolate reductase

2008-01-16T13:42:06Z

Tzvia Selzer:

[[Image:.jpg|left|150px]] 
<applet load='1RX2.pdb' size='300' color='white' frame='true' spin='on' caption='DHFR' align='right' script='Dihydrofolate reductase'
'''3D structure of dihydrofolate reductase''' 
== The sole source of tetrahydrofolate (THF)==

DHFR is a ubiquitous enzyme found in all organisms. The primary physiological role of DHFR is maintenance of the intracellular levels of tetrahydrofolate, a precursor of cofactors required for the biosynthesis of purines, pyrimidines, and several amino acids.

The enzyme, which is the sole source of tetrahydrofolate catalyzes the reduction of 7,8-dihydrofolate (DHF) to 5,6,7,8-tetrahydrofolate (THF) by stereospecific hydride transfer from the NADPH cofactor to the C6 atom of the pterin ring with concomitant protonation at N5.
Being the sole source of THF it is an Achilles’ heel of rapidly proliferating cells, making it an attractive target of several important anticancer and antimicrobial drugs such as methotrexate, trimethoprim, and pyrimethamine.

Dihydrofolate reductase

2008-01-16T13:14:24Z

Tzvia Selzer:

DHFR is a ubiquitous enzyme found in all organisms. The primary physiological role of DHFR is maintenance of the intracellular levels of tetrahydrofolate, a precursor of cofactors required for the biosynthesis of purines, pyrimidines, and several amino acids.
<applet load='1RX2' size='300' color='white' frame='true' align='right' caption='DHFR:1RX2' script='false'/>
The enzyme, which is the sole source of tetrahydrofolate catalyzes the reduction of 7,8-dihydrofolate (DHF) to 5,6,7,8-tetrahydrofolate (THF) by stereospecific hydride transfer from the NADPH cofactor to the C6 atom of the pterin ring with concomitant protonation at N5.
Being the sole source of THF it is an Achilles’ heel of rapidly proliferating cells, making it an attractive target of several important anticancer and antimicrobial drugs such as methotrexate, trimethoprim, and pyrimethamine.

Dihydrofolate reductase

2008-01-16T13:13:09Z

Tzvia Selzer:

DHFR is a ubiquitous enzyme found in all organisms. The primary physiological role of DHFR is maintenance of the intracellular levels of tetrahydrofolate, a precursor of cofactors required for the biosynthesis of purines, pyrimidines, and several amino acids.
<applet load='1rx2' size='300' color='white' frame='true' align='right' caption='DHFR:1rx2' script='false'/>
The enzyme, which is the sole source of tetrahydrofolate catalyzes the reduction of 7,8-dihydrofolate (DHF) to 5,6,7,8-tetrahydrofolate (THF) by stereospecific hydride transfer from the NADPH cofactor to the C6 atom of the pterin ring with concomitant protonation at N5.
Being the sole source of THF it is an Achilles’ heel of rapidly proliferating cells, making it an attractive target of several important anticancer and antimicrobial drugs such as methotrexate, trimethoprim, and pyrimethamine.

Dihydrofolate reductase

2008-01-16T13:03:38Z

Tzvia Selzer:

DHFR is a ubiquitous enzyme found in all organisms. The primary physiological role of DHFR is maintenance of the intracellular levels of tetrahydrofolate, a precursor of cofactors required for the biosynthesis of purines, pyrimidines, and several amino acids. The enzyme, which is the sole source of tetrahydrofolate catalyzes the reduction of 7,8-dihydrofolate (DHF) to 5,6,7,8-tetrahydrofolate (THF) by stereospecific hydride transfer from the NADPH cofactor to the C6 atom of the pterin ring with concomitant protonation at N5.
Being the sole source of THF it is an Achilles’ heel of rapidly proliferating cells, making it an attractive target of several important anticancer and antimicrobial drugs such as methotrexate, trimethoprim, and pyrimethamine.