Proteopedia - User contributions [en]

Proteopedia:What's New

2012-05-28T18:41:08Z

Matthew Tugwell:

<big>What's New in Proteopedia?</big>
 
This page lists new pages, substantially updated pages, and new capabilities '''within''' Proteopedia. In contrast, [[Proteopedia:News]] lists '''external''' news such as adoptions, blogs, press, meetings, seminars and workshops about Proteopedia.

A major purpose of this page is to make it easier for users to find out about new user-created pages with substantial content. Only user-created pages that have substantial content (at least one paragraph of user-added text with three or more green links), and that are reasonably complete should be listed below. Pages that are started, but not yet completed, should not be listed until they are reasonably complete. Automatically seeded new pages, titled with PDB codes, are not listed here<ref>You can find new entries in the [[PDB]] by going to [http://www.rcsb.org RCSB] and searching by date range.</ref>. Minor updates to existing pages should not be listed.
<div style='float: right; width: 50%;'>
 
 
 
 
Please add new items at the top. If a linked page is not new, but has been updated with substantial new content, please say so. Each page's ''history'' tab (at the top) shows when it was created and the date of each update.
 
The left arrow symbol (<-) signifies a page that [[Help:Editing#Redirecting_One_Page_to_Another_Page|redirects]] to another page.
 
Because this page is maintained manually, the lists for recent months are usually incomplete. There are typically other new articles that are not yet listed. You may also wish to consult [[Topic pages]] (also maintained manually); [[Special:Newpages]] which is automatically generated, but includes the pages for new PDB entries seeded by the OCA robot; or [[Special:Allpages/a| all pages whose titles do not begin with a numeral]] (thus excluding pages titled with PDB codes, but not limited to new pages).
</div>

----
==2012==
===May 2012===
* [[Renin]]

==2011==
===May, 2011===
* [[RNase A]]
* [[RNase A Oligomers]]
* [[RNase A NMR]]
* [[RNaseA Nobel Prizes]]
* [[RNaseS RNaseB]]

===April, 2011===
*[[CASP]]
*[[Homology modeling]]
*[[Homology modeling servers]]
===March, 2011===
*[[Lac repressor]] has been updated to incorporate new understanding of interactions of proteins with the minor groove of DNA.
*[[Nitrotyrosine]], a post-translational modification occurring in inflammation that often inactivates enzymes.
*[[Java]]

==2010==
=== October, 2010 ===
*[[Psi and Phi Angles]], Identifies the atoms which make up these angles, illustrates how Jmol can be used to determine their values and by drawing planes illustrates how their values are set by rotating the plane of the peptide bonds and the alpha-carbons and the atoms bonded to them.

===July, 2010===
*[[Glutamate receptor (GluA2)|Glutamate Receptor]]

===June, 2010===
*[[Metal-Ligand Polyhedra]]: Mixtures of certain metal ions with bent bidentate ligands self-assemble into large polygons that can be functionalized to serve as receptors, nanoreactors, etc.

=== May, 2010 ===
*[[Rhodopsin]]

=== April, 2010 ===
*[[Green Fluorescent Protein]], significant additions have been made to this page.
*[[NADPH Cytochrome P450 Oxidoreductase]]
*[[Proteopedia:Twitter]] - Proteopedia is now on Twitter. '''Follow us at [http://twitter.com/proteopedia Proteopedia on Twitter]'''.
*[[Pore forming toxin, α-hemolysin|The pore forming toxin, α-hemolysin]]

=== March, 2010 ===
*[[Serine Proteases]], examines the structural basis of specificity and a general properties of the catalytic mechanism

=== January, 2010 ===
*[[Archaeal Histones]], illustrates the structural features of two histones and a dimer of one of them.
*[[Syn and anti nucleosides]], illustrates the structural differences in the syn and anti configurations of nucleosides.
*[[Ramachandran Plots]], this page is a copy of User:Karl Oberholser/Ramachandran Plots which is a protected page.
*[[LepA|''Escherichia coli'' LepA, the ribosomal back translocase]]

==2009==
===December, 2009===
''This month's list is incomplete:''
*[[User:Wayne Decatur/Interactions between Antibiotics and the Ribosome|Interactions between Antibiotics and the Ribosome]]
*[[Large Ribosomal Subunit of Haloarcula|Large Ribosomal Subunit of ''Haloarcula marismortui'']] 
*[[User:Wayne_Decatur/Haloarcula Large Ribosomal Subunit With Azithromycin|Azithromycin bound to the Large Ribosomal Subunit of Haloarcula]]
*[[Reverse transcriptase]]

===November, 2009===
''This month's list is incomplete:''
*[[1gm5|RecG in complex with a synthetic three-way DNA junction resembling a stalled replication fork]]
*[[3ews|DExD/H-box RNA-dependent ATPase DDX19 in the open]] and [[3g0h|closed]] cleft conformation

===October, 2009===
''This month's list is incomplete:''
*[[Ribosome]], also featured at the [[Main Page]], since its structures won the [[Nobel Prizes for 3D Molecular Structure|Nobel Prize in Chemistry]] this month!
*[[Intrinsically Unfolded Proteins (IUP)]]
*[[Extremophiles]]
*[[Proteopedia:Guidelines for Ethical Writing]]

===July, 2009===
''This month's list is incomplete:''
*[[Influenza hemagglutinin]]
*The 21st and 22nd amino acids were added to [[Amino Acids]]: namely [[Selenocysteine]] and [[Pyrrolysine]].

===March, 2009===
''This month's list is incomplete:''
*[[Mechanosensitive channels: opening and closing]] includes morphs of the ion-conducting channel opening and closing.
*[[High school teachers' resources]]
*[[Richards, Frederic M.]] (1925-2009) including a photo of "Fred's Folly".

===February, 2009===
''This month's list is incomplete:''
*[[Ion channels]] is an attempt to cover a family of proteins and list their available PDB structures.

===January, 2009===
''This month's list is incomplete:''

==2008==
===December, 2008===
*[[Conservation, Evolutionary]] now includes instructions on how to show a ConSurf result as a scene in Proteopedia, complete with the standard ConSurf color key.
*[[Resolution]] now includes a movie illustrating the relation between the atomic model and the electron density map while resolution ranges from 0.5 to 5.0 Ångstroms.

===November, 2008===
*[[Suppression of RNA Silencing by Viruses|RNA silencing: suppression by viruses]]. Concerns the research awarded the [http://nobelprize.org/nobel_prizes/medicine/laureates/2006/ 2006 Nobel Prize in Physiology or Medicine]. Linked are new pages on specific RNA silencing proteins: [[Plant Viral Protein p19 Suppression of RNA Silencing|Plant viral protein p19]], [[Tomato aspermy virus protein 2b Suppression of RNA Silencing|Tomato aspermy virus protein 2b]], and [[Flock house virus B2 protein Suppression of RNA Silencing|Flock house virus B2 protein]].
*[[Transcription Termination Factor Rho]].
*Mechanosensitive ion channel of large conductance, with open, intermediate, and closed conformations, [[2oar]].
*Crucial role of electrostatic features in halotolerance of carbonic anhydrase, [[1y7w]].
*[[Hydrogen in macromolecular models]]
*[[Molecular modeling and visualization software]], whick links to new pages on [[PyMOL]], [[Jmol]], [[RasMol]], and [[Chime]].

===October, 2008===
*[[Lac repressor]] structure, including a morph of the DNA-binding domain bending the operator DNA.
*Poly(A) Polymerase, [[2q66]]: A new section complementing this month's article in [[Molecule of the Month]].
*[[Structure Gallery Generator]] generates galleries of thumbnail molecular images, linked to Proteopedia, for external websites or within Proteopedia pages.
*Acetylcholinesterase in complex with anti-Alzheimer's drug candidates: Crystal packing mediates enantioselective ligand recognition, [[1zgb]].
*Thermal stability analysis of alcohol dehydrogenase: [[2oui]], [[2nvb]].
*Confirmation of a heterodimer predicted by computational genomic analysis (neither chain could be crystallized alone): [[2g38]].
*Complex Of ''S. griseus'' Proteinase B And Polypeptide Chymotrypsin Inhibitor-1 From Russet Burbank Potato Tubers, [[4sgb]].
*''Structures Saving the Most Lives'' is a new list added to the [[Highest impact structures]] page originally created in February, 2008.
*[[Hydrogen bonds]]
*[[Nobel Prizes for 3D Molecular Structure]]
*[[Morphs]]: Although this page was created in March, 2008, most of its content was added this month.
*[[Proteopedia: Email list]]
*[[Proteopedia:What's New|What's New in Proteopedia?]] (this page).
*Several pages about visualization software: [[FirstGlance in Jmol]], [[Swiss-PDBViewer = DeepView]], and [[Protein Explorer]].

===September, 2008===
*Anticancer Prodrug CPT-11 complexed with ''Torpedo californica'' Acetylcholinesterase [[1u65]]
*[[Avian Influenza Neuraminidase, Tamiflu and Relenza]]
*Insecticidal delta-endotoxin [[Cyt2Ba]] from ''Bacillus thuringiensis''.
*TEM1-β-Lactamase/ β-Lactamase Inhibitor Protein (BLIP), [[2b5r]] and [[1s0w]].
*Acid-beta-glucosidase covalently bound to conduritol B epoxide, [[1y7v]].
*Ribonuclease A, [[1rta]] has a new section complementing this month's article in [[Molecule of the Month]].
*[[DRuMS]], standard color schemes for macromolecules, and color key templates for use in Proteopedia.
*[[User:Tom Gluick/glutamine synthetase|Glutamine Synthetase]], which includes instructions on how to use the Jmol console for advanced scene authoring.

===August, 2008===
*[[HIV-1 protease]]
*[[Pyruvate phosphate dikinase]] with a morph of the catalytic reaction and conformational changes.
*[[Enzyme I of the Phosphoenolpyruvate:Sugar Phosphotransferase System]] with a morph of the catalytic reaction and conformational changes.
*[[Antizyme Inhibitor]]
*Selenocysteine Synthase, [[SelB]] is a new page complementing this month's article in [[Molecule of the Month]].
*[[Teaching Strategies Using Proteopedia‎]]
*[[User:J._Shaun_Lott/BIOSCI_203|Protein structure lesson plan for BioSci 203]]
*[[Proteopedia: News]]

===July, 2008===
*[[Biotin Protein Ligase]]
*YAGE, A Prophage Protein Belonging To The Dihydrodipicolinic Acid Synthase Family From E. Coli K12, [[2v9d]].
*[[User:Karl_Oberholser/Ramachandran_Plots|Ramachandran Plots]]
*[[Flexibility of aromatic residues in acetylcholinesterase]]
*Horizontal gene transfer ssDNA binding protein from ''Agrobacterium tumefaciens'' [[VirE1/VirE2]]=[[3btp]]
*[[Proteopedia:Page of the Year Competition]]
*[[Student Projects]]

===June 2008===
*Computational design of a Kemp elimination catalyst [[2rkx]].
*[[Recoverin, a calcium-activated myristoyl switch‎]]
*G protein, ras oncogene: [[James_D_Watson/Proteins_Intro]].
*[[Ribulose-1,5-bisphosphate carboxylase/oxygenase]] uses the Kinemage applet.
*[[Acid-beta-glucosidase]]
*[[Rop protein]]

*[[Institute of Clinical Biochemistry]], Oslo, Norway.
*[[Research Groups]] <- [[Institutes]]
*[[Teaching Scenes, Tutorials, and Educators' Pages‎]]

'''About Macromolecular Structure'''
*[[About Macromolecular Structure]] <- [[About Protein Structure]]
*[[Amino Acids]]
*[[Asymmetric Unit]]
*[[Atomic coordinate file]]
*[[Biological Unit]] <- [[Quaternary structure]]
*[[Free R]]
*[[NMR Ensembles of Models‎]]
*[[PDB identification code]]
*[[Quality assessment for molecular models]]
*[[R value]]
*[[Resolution]]
*[[Temperature value]] <- [[Disorder]], [[B value]]
*[[Unit cell]]

===May 2008===
*[[Acetylcholinesterase]]
*[[2ace]] with an overview of the significance of this, the first acetylcholinesterase structure.
*Anti-Alzheimer's drug, Aricept, complexed with acetylcholinesterase [[1eve]].
*Tacrine Binding To Aromatic Residues In The Active-site Gorge Of Acetylcholinesterase, [[1acj]].
*Serum Paraoxonase-1 (PON1) via directed evolution [[1v04]].
*Human acid-beta-glucosidase, [[1ogs]].
*[[Photosystem II]], an undergraduate project.
*[[Ozonolysis]]: cool animation of a chemical reaction!

*[[Help:Copying FirstGlance Scenes into Proteopedia]]

===April 2008===
*Acetylcholinesterase inhibited by nerve agent soman [[1som]].
*Highest resolution acetylcholinesterase so far, [[1ea5]].
*Tetramerization domain of acetylcholinesterase [[1vzj]].
*Locations of mutations in oncogene phosphatidylinositol 3-kinase [[2rd0]], with many of the published figures made interactive in Jmol.
*Escherichia coli GlpG, an integral membrane protein rhomboid protease, unique in cleaving the transmembrane domains of other membrane proteins, [[2ic8]].
*[[Major Histocompatibility Complex Class I]] (no Jmol yet)
*[[Personal favorites]]
*[[Believe It or Not!]]
*[[Help:Protected Pages]]

===March 2008===
*Conformational flexibility in the peripheral site of Torpedo californica acetylecholinesterase revealed by the complex structure with a bifunctional inhibitor, [[2cek]].
*[[Proton Channels]]
*[[Proteopedia:Namespaces]]
*[[Proteopedia:About]]
*[[SGAP]] Streptomyces griseus Aminopeptidase (SGAP) (''no Jmol'')

===February 2008===
*[[Hemoglobin]]
*[[Highest impact structures]] of all time.
*[[Nucleosomes]]
*Scorpion alpha-toxin [[1qlh]].
*[[Peptide]]
*[[Proteopedia:Problems]]
*[[Personal favorites]]

===January 2008===
*[[AChE inhibitors and substrates]]
*[[Dihydrofolate reductase]]

==2007==
===October-December 2007===
*[[Serine Protease]]
*[[Nqo1]] NADH quinone oxidoreductase (NQO1) in complex with its potent inhibitor dicoumarol.
*[[1xjo]] ''S. griseus'' aminopeptidase.
*[[Glycine]]
*[[Bacterial Intein-Like Domains (BILs)]] (no Jmol, no green links)
*[[Hint auto-proteolytic protein-processing domains]] (no Jmol, no green links)

==See Also==

*[[Proteopedia:News]]
*[[Proteopedia: Email list]]
*[[Special:Newpages|Newest Pages]] appears to list only the current month, and mostly automatically seeded pages.
*[[Special:Recentchanges|Most Recent Changes]]
*[[Topic pages]]

==Notes==
<references />

Renin

2012-05-28T18:37:27Z

Matthew Tugwell:

[[Image:ColoredRenin.png|thumb|530px|alt=text|Renin]]

Renin, also known as angiotensinogenase, is an aspartyl protease and belongs to the protein family peptidase A1. Aspartyl proteases are endopeptidases that typically use two aspartate residues in the active site to specifically cleave peptide substrates using an acid-base hydrolysis mechanism. Mature renin circulates in the blood stream and contains 340 amino acid residues and has a mass of approximately 37 kDa. The function of renin is to cleave angiotensinogen to produce angiotensin I.

Renin is secreted by the kidneys. The kidneys act both directly and indirectly to regulate arterial blood pressure and provide the major long term mechanism of blood pressure and control. The direct mechanism changes blood volume independently of hormones. When blood pressure and blood volume increase the kidneys can not filter all of the liquids and thus liquids are lost in the urine to decrease blood pressure and blood volume.

The indirect mechanism, or the [http://en.wikipedia.org/wiki/Renin-angiotensin_system renin-angiotensin system] (RAS), controls blood volume and blood pressure through renin and two forms of [http://en.wikipedia.org/wiki/Angiotensin angiotensin]. Renin is involved in the rate limiting first step of a cascade that eventually produces angiotensin II. The specialized granular cells of the [http://en.wikipedia.org/wiki/Juxtaglomerular_apparatus juxtaglomerular apparatus] secrete renin when stimulated by the [http://en.wikipedia.org/wiki/Macula_densa macula densa] when blood pressure or blood volume decreases. Renin circulating in the blood stream cleaves a small 10 residue portion of plasma protein angiotensinogen that is secreted by the liver. Cleavage of angiotensinogen produces the inactive precursor angiotensin I that is converted to angiotensin II by [http://en.wikipedia.org/wiki/Angiotensin-converting_enzyme angiotensin-converting enzyme] primarily in the lungs. Angiotensin II increases blood pressure in three ways.
:*Angiotensin II constricts blood vessels by influencing smooth muscle tissue. The heart pumps faster to overcome the constricted arteries and blood pressure rises.
:*Angiotensin II stimulates the [http://en.wikipedia.org/wiki/Adrenal_cortex adrenal cortex] to secrete [http://en.wikipedia.org/wiki/Aldosterone aldosterone] that causes renal adsorption of sodium. When sodium moves into the blood stream water follows to increase the blood volume.
:*Angiotensin II causes the [http://en.wikipedia.org/wiki/Posterior_pituitary posterior pituitary gland] to release [http://en.wikipedia.org/wiki/Vasopressin vasopressin], also known as antidiuretic hormone, to induce water reabsorption.
Additionally, angiotensin II triggers the sensation of thirst.

The release of renin into the blood stream ultimately raises blood pressure. The kidneys restore and maintain blood pressure homeostasis by regulating blood volume through the action of renin. Although blood volume varies with age, body size, and sex, renal mechanisms usually maintain it to 5 liters.

Renin has been identified in many eukaryotic organisms including; humans, mice, marmosets, monkeys, chimpanzees, macaques, dogs, rats, frogs, and zebrafish. The function of renin in all organisms is similar, but the sequence and peptide length vary slightly.

Renin is important clinically because [http://en.wikipedia.org/wiki/Renin_inhibitor renin inhibitors], such as [http://en.wikipedia.org/wiki/Aliskiren aliskiren], can be used to treat hypertension.

==Structure==

<Structure load='2ren' size='400' frame='true' align='left' caption='Mature Renin' scene='Insert optional scene name here' />
The precursor of renin is a 406 amino acid residue protein. <scene name='Sandbox_Reserved_489/Signal_domain/1'>Residues 1-23</scene> are a signal peptide sequence and residues 24-66 are cleaved to produce the mature 340 amino acid residue <scene name='Sandbox_Reserved_489/Mature_renin/1'>mature renin</scene>. The secondary structural elements of renin include 29 <scene name='Sandbox_Reserved_489/Betasheetscolors/1'> antiparallel β sheets</scene>, 3 <scene name='Sandbox_Reserved_489/Betabridges/1'> β bridges</scene>, 4 <scene name='Sandbox_Reserved_489/Alphahelixes/1'> α helices</scene>, <scene name='Sandbox_Reserved_489/310heleices/1'> 2 </scene>310<scene name='Sandbox_Reserved_489/310heleices/1'> helices</scene>, and <scene name='Sandbox_Reserved_489/Turns/1'>18 turns</scene>. The most impressive structural feature of renin is the antiparallel <scene name='Sandbox_Reserved_489/Betasheetspiral/1'> β sheet</scene> that forms the two similar lobes of renin. <scene name='Sandbox_Reserved_489/Hydrophobichydrophillic/1'>Hydrophilic (blue) and hydrophobic (red) residues</scene> are located primarily on the outside and inside portions of renin respectively. The most important structure is the <scene name='Sandbox_Reserved_489/Hydrophobicactivesite/1'>hydrophobic pocket</scene> located in the active site that allows substrate binding. The active site of renin contains two essential <scene name='Sandbox_Reserved_489/Activesiteasps2/2'>aspartate residues</scene>. Renin has <scene name='Sandbox_Reserved_489/Catalyticmotifs/1'>two catalytic motifs</scene> after each of the two aspartate residues. Renin also uses a <scene name='Sandbox_Reserved_489/Activesiteflap/1'>active site flap</scene>, a β hairpin structure, that open and closes to uncover or cover the active site.

Post translational modifications of renin include; precursor cleavage of propetide to produce active mature renin, disulfide bond formation, and glycosylation of certain residues. Disulfide bonds are formed to connect serine residues <scene name='Sandbox_Reserved_489/Disulfidebond1/2'>51 to 58</scene>, <scene name='Sandbox_Reserved_489/Disulfidebond2/2'>217 to 221</scene>, and <scene name='Sandbox_Reserved_489/Disulfidebond3/2'>259 to 296</scene>. <scene name='Sandbox_Reserved_489/Glycosylated/2'>Two asparagine residues</scene> at positions 14 and 75 can be glycosylated. The asparagine residue at postion 75 is glycosylated (2-(acetylamino)-2-deoxy-A-D-glucopyranose) in mature renin whereas the residue at postion 14 is not glycosylated.<ref>Margrane M. and the UnitProt consortium, '''Uniprot Knowledgebase: a hub of integrated protein data''', Database, 2012: bar009 (2011). Public Accession Number P00797 </ref>

The structure of recombinant human renin has been solved using X-ray diffraction at 2.5 Å resolution.<ref>PMID: 2493678</ref>

==Function==
[[Image:AspartylProteaseMechanism.jpg|thumb|510px|alt=text|Aspartyl Protease Mechanism<ref>PMID:3313384</ref>]]
Renin secretion is stimulated by a decrease in arterial blood pressure, a decrease in sodium chloride levels in kidney [http://en.wikipedia.org/wiki/Nephron nephrons], or [http://en.wikipedia.org/wiki/Sympathetic_nervous_system sympathetic nervous system] activity.

The substrate of renin, angiotensinogen, is a 452 amino acid residue in humans. Renin utilizes two aspartate residues in the <scene name='Sandbox_Reserved_489/Activesiteasps2/2'>active site</scene> to cleave the peptide bond between leucine and valine residues on angiotensinogen. Angiotensin I is an inactive short peptide of 10 amino acids that is produced by the renin cleavage reaction. The close proximity of the two aspartate allows the acid-base hydrolysis mechanism to cleave the peptide bond. Because the aspartate residues are close together one residue has a higher pKa and the other residue has a lower pKa. The mechanism of the catalysis is an acid-base transfer of water between the two aspartate residues. There is a water molecule associated with the two aspartate residues in the active site and also a water associated with the peptide bond that is cleaved. Initially one aspartate residue carbonyl is deprotonated and the other is protonated. The deprotonated aspartate removes a proton from water allowing the water to attack the carbonyl of the peptide bond in the substrate forming a tetrahedral oxyanion intermediate on the substrate. Rearrangement of the intermediate causes protonation of the amide on the substrate completing the cleavage reaction. A concerted mechanism of action has also been proposed that states the active site aspartate and water attack the scissle peptide bond in a single step with no covalent tetrahedral intermediate, while still forming the tetrahedral transition state.

Renin can also bind the renin receptor [http://en.wikipedia.org/wiki/ATP6AP2 ATPase H(+)-transporting lysosomal accessory protein 2] (ATP6AP2) to convert angiotensinogen to angiotensin I at a much faster rate.<ref>PMID: 12045255</ref>

==Renin Inhibitors==
[[Image:Aliskiren.jpg|thumb|400px|alt=text|Aliskiren<ref>PMID:15723979</ref>]]
<Structure load='2v0z' size='300' frame='true' align='left' caption='Asymetric Unit of Renin with Bound Aliskiren' scene='Sandbox_Reserved_489/Asymetricunit2v0z/1' />
There are three generations of renin inhibitors. The first two generation molecules were peptide molecules. These peptide molecules were not specific or effective as renin inhibitors. Aliskiren, part of the 3rd generation, is a nonpeptide renin inhibitor. Small molecule nonpeptide inhibitors such as aliskiren have good pharmokenetics and are very specific for renin and not other protein peptidases. Advancements in crystallography and molecular modeling allowed the discovery of aliskiren. Aliskiren inhibits renin activity. Since renin is the rate limiting step of the RAS renin inhibition is a successful method to lower blood pressure.

Aliskiren is a hydrophilic molecule. When bound to renin, aliskiren occupies the S1, S1', S2', and S3 hydrophobic regions of renin. Most importantly aliskiren occupies the S3SP region that is equally hydrophobic and hydrophilic and greatly increases binding affinity.<ref>PMID: 20731374</ref> Aliskiren interacts with multiple residues in renin. The hydroxyl group hydrogen bonds both <scene name='Sandbox_Reserved_489/Asp32/2'>aspartate 32</scene> oxygens. The amine group hydrogen bonds carboxylic acid group of <scene name='Sandbox_Reserved_489/Asp32andgly132/1'>glycine 217 and the oxygen atom of asparate 32</scene>. The methoxy group in the S3 hydrophobic region hydrogen bonds to secondary amine group of <scene name='Sandbox_Reserved_489/Tyr14/2'>tyrosine 14</scene>. The amide group hydrogen bonds with the secondary amine of <scene name='Sandbox_Reserved_489/Ser76/2'>serine 76</scene>.<ref>PMID: 20855222</ref> And the terminal amide hydrogen bonds with <scene name='Sandbox_Reserved_489/Arg_74/1'>arginine 74</scene> in the S2' hydrophobic pocket.<ref>PMID: 21708467</ref>

Aliskiren is approved by the [http://www.fda.gov/ Federal Drug Administration (FDA)] to treat hypertension.

However, there are certain drug combinations that can be dangerous in combination with aliskiren. The FDA announced on April 20, 2012 that patients with [http://en.wikipedia.org/wiki/Diabetes_mellitus diabetes] should not be prescribed drugs containing aliskiren in combination with [http://en.wikipedia.org/wiki/ACE_inhibitor angiotensin-converting-enzyme (ACE) inhibitors] and [http://en.wikipedia.org/wiki/Angiotensin_II_receptor_antagonist angiotensin receptor blockers (ARBs)]. Examples of drugs that combine aliskiren with other drugs include valturna, tekturna HCT, tekamlo, and amturnide. The drug combinations increase the risk of renal impairment, hypotension, hyperkalemia, and lack of efficacy in diabetes patients. The drug combinations should also be avoided in patients with renal impairments. The announcement was based on a [http://www.novartis.com/ Novartis]-sponsored clinical trial called Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE). The FDA also stated that preliminary ALTITUDE data indicated an increase in cardiovascular risks such as stroke and death but further trial results are necessary to confirm these risks.<ref>Lowes, Robert. "Aliskiren in Certain Rx Combos Nixed for Diabetic Patients." ''Webscape Medical News.'' Web MD, 2012. 20 April 2012. <[http://www.medscape.com/viewarticle/762425 http://www.medscape.com/viewarticle/762425]></ref>

The structure of renin bound with the inhibitor aliskiren has been solved using X-ray diffraction at 3.0 Å resolution.<ref>PMID: 10903938</ref>

==Diseases==

Renal tubular dysgenisis is caused by defects in the renin gene. Renal tubular dysgenisis is an autosomal recessive disorder of renal tubular developement and is characterized by persistant fetal anuria and perinatal death. The RAS plays a crucial role in the developement of the kidneys during early fetal life. <ref>PMID:1611425</ref>

Familial juvenile hyperuricemic nephropathy type 2 is also caused by defects in the renin gene. Familial juvenile hyperuricemic nephropathy type 2 is characterized by slowly progressive renal failure and anemia. The autosomal dominant disorder is caused by a deletion of leucine 16 or a mutation of leucine 16 to arginine. The mutations effect the hydrophobicity of the signal sequence and disrupt the proper transport of preprorenin into the endoplasmic reticulum and thus effecting prerenin processing. The mutatnt proteins are toxic and reduce the viability of renin expressing cells, eventually causing renal failure.<ref>PMID:19664745</ref>
==References==
<references />

Renin

2012-05-28T18:36:51Z

Matthew Tugwell: New page: Renin ---- Renin Renin, also known as angiotensinogenase, is an aspartyl protease and belongs to the pr...

Renin
----
[[Image:ColoredRenin.png|thumb|530px|alt=text|Renin]]

Renin, also known as angiotensinogenase, is an aspartyl protease and belongs to the protein family peptidase A1. Aspartyl proteases are endopeptidases that typically use two aspartate residues in the active site to specifically cleave peptide substrates using an acid-base hydrolysis mechanism. Mature renin circulates in the blood stream and contains 340 amino acid residues and has a mass of approximately 37 kDa. The function of renin is to cleave angiotensinogen to produce angiotensin I.

Renin is secreted by the kidneys. The kidneys act both directly and indirectly to regulate arterial blood pressure and provide the major long term mechanism of blood pressure and control. The direct mechanism changes blood volume independently of hormones. When blood pressure and blood volume increase the kidneys can not filter all of the liquids and thus liquids are lost in the urine to decrease blood pressure and blood volume.

The indirect mechanism, or the [http://en.wikipedia.org/wiki/Renin-angiotensin_system renin-angiotensin system] (RAS), controls blood volume and blood pressure through renin and two forms of [http://en.wikipedia.org/wiki/Angiotensin angiotensin]. Renin is involved in the rate limiting first step of a cascade that eventually produces angiotensin II. The specialized granular cells of the [http://en.wikipedia.org/wiki/Juxtaglomerular_apparatus juxtaglomerular apparatus] secrete renin when stimulated by the [http://en.wikipedia.org/wiki/Macula_densa macula densa] when blood pressure or blood volume decreases. Renin circulating in the blood stream cleaves a small 10 residue portion of plasma protein angiotensinogen that is secreted by the liver. Cleavage of angiotensinogen produces the inactive precursor angiotensin I that is converted to angiotensin II by [http://en.wikipedia.org/wiki/Angiotensin-converting_enzyme angiotensin-converting enzyme] primarily in the lungs. Angiotensin II increases blood pressure in three ways.
:*Angiotensin II constricts blood vessels by influencing smooth muscle tissue. The heart pumps faster to overcome the constricted arteries and blood pressure rises.
:*Angiotensin II stimulates the [http://en.wikipedia.org/wiki/Adrenal_cortex adrenal cortex] to secrete [http://en.wikipedia.org/wiki/Aldosterone aldosterone] that causes renal adsorption of sodium. When sodium moves into the blood stream water follows to increase the blood volume.
:*Angiotensin II causes the [http://en.wikipedia.org/wiki/Posterior_pituitary posterior pituitary gland] to release [http://en.wikipedia.org/wiki/Vasopressin vasopressin], also known as antidiuretic hormone, to induce water reabsorption.
Additionally, angiotensin II triggers the sensation of thirst.

The release of renin into the blood stream ultimately raises blood pressure. The kidneys restore and maintain blood pressure homeostasis by regulating blood volume through the action of renin. Although blood volume varies with age, body size, and sex, renal mechanisms usually maintain it to 5 liters.

Renin has been identified in many eukaryotic organisms including; humans, mice, marmosets, monkeys, chimpanzees, macaques, dogs, rats, frogs, and zebrafish. The function of renin in all organisms is similar, but the sequence and peptide length vary slightly.

Renin is important clinically because [http://en.wikipedia.org/wiki/Renin_inhibitor renin inhibitors], such as [http://en.wikipedia.org/wiki/Aliskiren aliskiren], can be used to treat hypertension.

==Structure==

<Structure load='2ren' size='400' frame='true' align='left' caption='Mature Renin' scene='Insert optional scene name here' />
The precursor of renin is a 406 amino acid residue protein. <scene name='Sandbox_Reserved_489/Signal_domain/1'>Residues 1-23</scene> are a signal peptide sequence and residues 24-66 are cleaved to produce the mature 340 amino acid residue <scene name='Sandbox_Reserved_489/Mature_renin/1'>mature renin</scene>. The secondary structural elements of renin include 29 <scene name='Sandbox_Reserved_489/Betasheetscolors/1'> antiparallel β sheets</scene>, 3 <scene name='Sandbox_Reserved_489/Betabridges/1'> β bridges</scene>, 4 <scene name='Sandbox_Reserved_489/Alphahelixes/1'> α helices</scene>, <scene name='Sandbox_Reserved_489/310heleices/1'> 2 </scene>310<scene name='Sandbox_Reserved_489/310heleices/1'> helices</scene>, and <scene name='Sandbox_Reserved_489/Turns/1'>18 turns</scene>. The most impressive structural feature of renin is the antiparallel <scene name='Sandbox_Reserved_489/Betasheetspiral/1'> β sheet</scene> that forms the two similar lobes of renin. <scene name='Sandbox_Reserved_489/Hydrophobichydrophillic/1'>Hydrophilic (blue) and hydrophobic (red) residues</scene> are located primarily on the outside and inside portions of renin respectively. The most important structure is the <scene name='Sandbox_Reserved_489/Hydrophobicactivesite/1'>hydrophobic pocket</scene> located in the active site that allows substrate binding. The active site of renin contains two essential <scene name='Sandbox_Reserved_489/Activesiteasps2/2'>aspartate residues</scene>. Renin has <scene name='Sandbox_Reserved_489/Catalyticmotifs/1'>two catalytic motifs</scene> after each of the two aspartate residues. Renin also uses a <scene name='Sandbox_Reserved_489/Activesiteflap/1'>active site flap</scene>, a β hairpin structure, that open and closes to uncover or cover the active site.

Post translational modifications of renin include; precursor cleavage of propetide to produce active mature renin, disulfide bond formation, and glycosylation of certain residues. Disulfide bonds are formed to connect serine residues <scene name='Sandbox_Reserved_489/Disulfidebond1/2'>51 to 58</scene>, <scene name='Sandbox_Reserved_489/Disulfidebond2/2'>217 to 221</scene>, and <scene name='Sandbox_Reserved_489/Disulfidebond3/2'>259 to 296</scene>. <scene name='Sandbox_Reserved_489/Glycosylated/2'>Two asparagine residues</scene> at positions 14 and 75 can be glycosylated. The asparagine residue at postion 75 is glycosylated (2-(acetylamino)-2-deoxy-A-D-glucopyranose) in mature renin whereas the residue at postion 14 is not glycosylated.<ref>Margrane M. and the UnitProt consortium, '''Uniprot Knowledgebase: a hub of integrated protein data''', Database, 2012: bar009 (2011). Public Accession Number P00797 </ref>

The structure of recombinant human renin has been solved using X-ray diffraction at 2.5 Å resolution.<ref>PMID: 2493678</ref>

==Function==
[[Image:AspartylProteaseMechanism.jpg|thumb|510px|alt=text|Aspartyl Protease Mechanism<ref>PMID:3313384</ref>]]
Renin secretion is stimulated by a decrease in arterial blood pressure, a decrease in sodium chloride levels in kidney [http://en.wikipedia.org/wiki/Nephron nephrons], or [http://en.wikipedia.org/wiki/Sympathetic_nervous_system sympathetic nervous system] activity.

The substrate of renin, angiotensinogen, is a 452 amino acid residue in humans. Renin utilizes two aspartate residues in the <scene name='Sandbox_Reserved_489/Activesiteasps2/2'>active site</scene> to cleave the peptide bond between leucine and valine residues on angiotensinogen. Angiotensin I is an inactive short peptide of 10 amino acids that is produced by the renin cleavage reaction. The close proximity of the two aspartate allows the acid-base hydrolysis mechanism to cleave the peptide bond. Because the aspartate residues are close together one residue has a higher pKa and the other residue has a lower pKa. The mechanism of the catalysis is an acid-base transfer of water between the two aspartate residues. There is a water molecule associated with the two aspartate residues in the active site and also a water associated with the peptide bond that is cleaved. Initially one aspartate residue carbonyl is deprotonated and the other is protonated. The deprotonated aspartate removes a proton from water allowing the water to attack the carbonyl of the peptide bond in the substrate forming a tetrahedral oxyanion intermediate on the substrate. Rearrangement of the intermediate causes protonation of the amide on the substrate completing the cleavage reaction. A concerted mechanism of action has also been proposed that states the active site aspartate and water attack the scissle peptide bond in a single step with no covalent tetrahedral intermediate, while still forming the tetrahedral transition state.

Renin can also bind the renin receptor [http://en.wikipedia.org/wiki/ATP6AP2 ATPase H(+)-transporting lysosomal accessory protein 2] (ATP6AP2) to convert angiotensinogen to angiotensin I at a much faster rate.<ref>PMID: 12045255</ref>

==Renin Inhibitors==
[[Image:Aliskiren.jpg|thumb|400px|alt=text|Aliskiren<ref>PMID:15723979</ref>]]
<Structure load='2v0z' size='300' frame='true' align='left' caption='Asymetric Unit of Renin with Bound Aliskiren' scene='Sandbox_Reserved_489/Asymetricunit2v0z/1' />
There are three generations of renin inhibitors. The first two generation molecules were peptide molecules. These peptide molecules were not specific or effective as renin inhibitors. Aliskiren, part of the 3rd generation, is a nonpeptide renin inhibitor. Small molecule nonpeptide inhibitors such as aliskiren have good pharmokenetics and are very specific for renin and not other protein peptidases. Advancements in crystallography and molecular modeling allowed the discovery of aliskiren. Aliskiren inhibits renin activity. Since renin is the rate limiting step of the RAS renin inhibition is a successful method to lower blood pressure.

Aliskiren is a hydrophilic molecule. When bound to renin, aliskiren occupies the S1, S1', S2', and S3 hydrophobic regions of renin. Most importantly aliskiren occupies the S3SP region that is equally hydrophobic and hydrophilic and greatly increases binding affinity.<ref>PMID: 20731374</ref> Aliskiren interacts with multiple residues in renin. The hydroxyl group hydrogen bonds both <scene name='Sandbox_Reserved_489/Asp32/2'>aspartate 32</scene> oxygens. The amine group hydrogen bonds carboxylic acid group of <scene name='Sandbox_Reserved_489/Asp32andgly132/1'>glycine 217 and the oxygen atom of asparate 32</scene>. The methoxy group in the S3 hydrophobic region hydrogen bonds to secondary amine group of <scene name='Sandbox_Reserved_489/Tyr14/2'>tyrosine 14</scene>. The amide group hydrogen bonds with the secondary amine of <scene name='Sandbox_Reserved_489/Ser76/2'>serine 76</scene>.<ref>PMID: 20855222</ref> And the terminal amide hydrogen bonds with <scene name='Sandbox_Reserved_489/Arg_74/1'>arginine 74</scene> in the S2' hydrophobic pocket.<ref>PMID: 21708467</ref>

Aliskiren is approved by the [http://www.fda.gov/ Federal Drug Administration (FDA)] to treat hypertension.

However, there are certain drug combinations that can be dangerous in combination with aliskiren. The FDA announced on April 20, 2012 that patients with [http://en.wikipedia.org/wiki/Diabetes_mellitus diabetes] should not be prescribed drugs containing aliskiren in combination with [http://en.wikipedia.org/wiki/ACE_inhibitor angiotensin-converting-enzyme (ACE) inhibitors] and [http://en.wikipedia.org/wiki/Angiotensin_II_receptor_antagonist angiotensin receptor blockers (ARBs)]. Examples of drugs that combine aliskiren with other drugs include valturna, tekturna HCT, tekamlo, and amturnide. The drug combinations increase the risk of renal impairment, hypotension, hyperkalemia, and lack of efficacy in diabetes patients. The drug combinations should also be avoided in patients with renal impairments. The announcement was based on a [http://www.novartis.com/ Novartis]-sponsored clinical trial called Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE). The FDA also stated that preliminary ALTITUDE data indicated an increase in cardiovascular risks such as stroke and death but further trial results are necessary to confirm these risks.<ref>Lowes, Robert. "Aliskiren in Certain Rx Combos Nixed for Diabetic Patients." ''Webscape Medical News.'' Web MD, 2012. 20 April 2012. <[http://www.medscape.com/viewarticle/762425 http://www.medscape.com/viewarticle/762425]></ref>

The structure of renin bound with the inhibitor aliskiren has been solved using X-ray diffraction at 3.0 Å resolution.<ref>PMID: 10903938</ref>

==Diseases==

Renal tubular dysgenisis is caused by defects in the renin gene. Renal tubular dysgenisis is an autosomal recessive disorder of renal tubular developement and is characterized by persistant fetal anuria and perinatal death. The RAS plays a crucial role in the developement of the kidneys during early fetal life. <ref>PMID:1611425</ref>

Familial juvenile hyperuricemic nephropathy type 2 is also caused by defects in the renin gene. Familial juvenile hyperuricemic nephropathy type 2 is characterized by slowly progressive renal failure and anemia. The autosomal dominant disorder is caused by a deletion of leucine 16 or a mutation of leucine 16 to arginine. The mutations effect the hydrophobicity of the signal sequence and disrupt the proper transport of preprorenin into the endoplasmic reticulum and thus effecting prerenin processing. The mutatnt proteins are toxic and reduce the viability of renin expressing cells, eventually causing renal failure.<ref>PMID:19664745</ref>
==References==
<references />

2012-04-15T23:03:52Z

Matthew Tugwell:

{{Sandbox_Reserved_Robert_B_Rose_1}}


Renin
----

Renin, also known as angiotensinogenase, is an aspartyl protease and belongs to the protein family peptidase A1. Aspartyl proteases are endopeptidases that typically use two aspartate residues in the active site in a reduction-oxidation reaction with water to specifically cleave peptide substrates. Mature renin circulates in the blood and contains 340 amino acid residues and has a mass of approximately 37 kDa. The function of renin is to cleave the angiotensin I precursor, angiotensinogen, to produce angiotensin I.

Renin is secreted by the kidneys. The kidneys act both directly and indirectly to regulate arterial blood pressure and provide the major long term mechanism of blood pressure and control. The direct mechanism changes blood volume independently of hormones. When blood pressure and blood volume increase the kidneys can not filter all of the liquids and thus liquids are lost in the urine to decrease blood pressure and blood volume.

The indirect mechanism, or the [http://en.wikipedia.org/wiki/Renin-angiotensin_system renin-angiotensin system] (RAS), controls blood volume and blood pressure through renin and two forms of [http://en.wikipedia.org/wiki/Angiotensin angiotensin]. Renin is involved in the rate limiting first step of a cascade that eventually produces angiotensin II. The specialized granular cells of the [http://en.wikipedia.org/wiki/Juxtaglomerular_apparatus juxtaglomerular apparatus] secrete renin when stimulated by the [http://en.wikipedia.org/wiki/Macula_densa macula densa] when blood pressure or blood volume decreases. Renin circulating in the blood stream cleaves a small 10 residue portion of plasma protein angiotensinogen that is secreted by the liver. Cleavage of angiotensinogen produces the inactive precursor angiotensin I that is converted to angiotensin II by [http://en.wikipedia.org/wiki/Angiotensin-converting_enzyme angiotensin-converting enzyme] primarily in the lungs. Angiotensin II increases blood pressure in three ways.
:*Angiotensin II constricts blood vessels by influencing smooth muscle tissue. The heart pumps faster to overcome the constricted arteries and blood pressure rises.
:*Angiotensin II stimulates the [http://en.wikipedia.org/wiki/Adrenal_cortex adrenal cortex] to secrete [http://en.wikipedia.org/wiki/Aldosterone aldosterone] that causes renal adsorption of sodium. when sodium moves into the blood stream water follows to increase the blood volume.
:*Angiotensin II causes the [http://en.wikipedia.org/wiki/Posterior_pituitary posterior pituitary gland] to release [http://en.wikipedia.org/wiki/Vasopressin vasopressin], also known as antidiuretic hormone, to induce water reabsorption.
Additionally, angiotensin II triggers the sensation of thirst.

The release of renin into the blood stream ultimately raises blood pressure. The kidneys restore and maintain blood pressure homeostasis by regulating blood volume through the action of renin. Although blood volume varies with age, body size, and sex, renal mechanisms usually maintain it to 5 liters.

Renin has been identified in many eukaryotic organisms including; humans, mice, marmosets, monkeys, chimpanzees, macaques, dogs, rats, frogs, and zebrafish. The function of renin in all organisms is similar, but the sequence and peptide length vary slightly.

Renin is important clinically because [http://en.wikipedia.org/wiki/Renin_inhibitor renin inhibitors], such as [http://en.wikipedia.org/wiki/Aliskiren Aliskiren] can be used to treat hypertension.

==Structure==

<Structure load='2ren' size='400' frame='true' align='right' caption='Mature Renin' scene='Insert optional scene name here' />
The precursor of renin is a 406 amino acid residue protein. <scene name='Sandbox_Reserved_489/Signal_domain/1'>Residues 1-23</scene> are a signal peptide sequence and residues 24-66 are cleaved to produce the mature 340 amino acid residue <scene name='Sandbox_Reserved_489/Mature_renin/1'>mature renin</scene>. The secondary structural elements of renin include <scene name='Sandbox_Reserved_489/Betasheetscolors/1'>29 antiparallel beta sheets</scene>, <scene name='Sandbox_Reserved_489/Betabridges/1'>3 beta bridges</scene>, <scene name='Sandbox_Reserved_489/Alphahelixes/1'>4 alpha helices</scene>, <scene name='Sandbox_Reserved_489/310heleices/1'>2 3-10 helices</scene>, and <scene name='Sandbox_Reserved_489/Turns/1'>18 turns</scene>. The most impressive structural feature of renin is the <scene name='Sandbox_Reserved_489/Betasheetspiral/1'>antiparallel beta sheet</scene> that forms the two similar lobes of renin. <scene name='Sandbox_Reserved_489/Hydrophobichydrophillic/1'>Hydrophilic (blue) and hydrophobic (red) residues</scene> are located primarily on the outside and inside portions of renin respectively. The most important structure is the <scene name='Sandbox_Reserved_489/Hydrophobicactivesite/1'>hydrophobic pocket</scene> located in the active site that allows substrate binding. The active site of renin contains two essential <scene name='Sandbox_Reserved_489/Activesiteasps2/2'>aspartate residues</scene>. Renin has <scene name='Sandbox_Reserved_489/Catalyticmotifs/1'>two catalytic motifs</scene> after each of the two aspartate residues. Renin also uses a <scene name='Sandbox_Reserved_489/Activesiteflap/1'>active site flap</scene>, a beta hairpin structure, that open and closes to uncover or cover the active site.

Post translational modifications of renin include; precursor cleavage of propetide to produce active mature renin, disulfide bond formation, and glycosylation of certain residues. Disulfide bonds are form to connect serine residues <scene name='Sandbox_Reserved_489/Disulfidebond1/1'>51 to 58</scene>, <scene name='Sandbox_Reserved_489/Disulfidebond2/1'>217 to 221</scene>, and <scene name='Sandbox_Reserved_489/Disulfidebond3/1'>259 to 296</scene>. <scene name='Sandbox_Reserved_489/Glycosylated/2'>Two asparagine residues</scene> at positions 14 and 75 can be glycosylated. The asparagine residue at postion 75 is glycosylated (2-(acetylamino)-2-deoxy-A-D-glucopyranose) in mature renin whereas the residue at postion 14 is not glycosylated.<ref>Margrane M. and the UnitProt consortium, '''Uniprot Knowledgebase: a hub of integrated protein data''', Database, 2012: bar009 (2011). Public Accession Number P00797 </ref>

The structure of recombinant human renin has been solved using X-ray diffraction at 2.5 angstrom resolution.<ref>PMID: 2493678</ref>

==Function==

Renin secretion is stimulated by a decrease in arterial blood pressure, a decrease in sodium chloride levels in kidney [http://en.wikipedia.org/wiki/Nephron nephrons], or [http://en.wikipedia.org/wiki/Sympathetic_nervous_system sympathetic nervous system] activity.

The substrate of renin, angiotensinogen, is a 452 amino acid residue in humans. Renin utilizes two aspartate residues in the <scene name='Sandbox_Reserved_489/Activesiteasps2/2'>active site</scene> to cleave the peptide bond between leucine and valine residues on angiotensinogen. Angiotensin I is an inactive short peptide of 10 amino acids that is produced by the renin cleavage reaction. The two aspartate residues operate most efficiently at acidic pH because one of the carbonyl groups must be deprotonated to accept a proton from water. The mechanism of the catalysis is an acid base transfer of water between the two aspartate residues. Initially one aspartate residue carbonyl is deprotonated and the other is protonated. The deprotonated aspartate removes a proton from water allowing the water to attack the carbonyl of the beptide bond in the substrate forming a tetrahedral oxyanion intermediate on the substrate. Rearrangement of the intermediate causes protonation of the amide on the substrate completing the cleavage reaction.

Renin can also bind the renin receptor [http://en.wikipedia.org/wiki/ATP6AP2 ATPase H(+)-transporting lysosomal accessory protein 2] (ATP6AP2) to convert angiotensinogen to angiotensin I at a much greater rate.<ref>PMID: 12045255</ref>

==Renin Inhibitors==

<Structure load='2v0z' size='500' frame='true' align='right' caption='Asymetric Unit of Renin with Bound Aliskiren' scene='Sandbox_Reserved_489/Asymetricunit2v0z/1' />
There are three generations of renin inhibitors. The first two generation molecules were peptide molecules. These peptide molecules were not specific or effective as renin inhibitors. Aliskiren, part of the 3rd generation, is a nonpeptide renin inhibitor. Small molecule nonpeptide inhibitors such as Aliskiren have good pharmokenetics and are very specific for renin and not other protein peptidases. Advancements in crystallography and molecular modeling allowed the discovery of aliskiren. Aliskiren inhibits renin activity. Since renin is the rate limiting step of the RAS renin inhibition is a successful method to lower blood pressure.

Aliskiren is a hydrophilic molecule. When bound to renin, Aliskiren occupies the S1, S1', S2', and S3 hydrophobic regions of renin. Most importantly Aliskiren occupise the S3SP region that is equally hydrophobic and hydrophilic and greatly increases binding affinity.<ref>PMID: 20731374</ref> Aliskiren interacts with multiple residues in renin. The hydroxyl group hydrogen bonds both <scene name='Sandbox_Reserved_489/Asp32/1'>aspartate 32</scene> oxygens. The amine group hydrogen bonds carboxylic acid group of <scene name='Sandbox_Reserved_489/Asp32andgly132/1'>glycine 217 and the oxygen atom of asparate 32</scene>. The methoxy group in the S3 hydrophobic region hydrogen bonds to secondary amine group of <scene name='Sandbox_Reserved_489/Tyr14/1'>tyrosine 14</scene>. The amide group hydrogen bonds with the secondary amine of <scene name='Sandbox_Reserved_489/Ser76/2'>serine 76</scene>.<ref>PMID: 20855222</ref> And the terminal amide hydrogen bonds with <scene name='Sandbox_Reserved_489/Arg_74/1'>arginine 74</scene> in the S2' hydrophobic pocket.<ref>PMID: 21708467</ref>

Aliskiren is approved by the [http://www.fda.gov/ Federal Drug Administration] to treat hypertension.

The structure of renin bound with the inhibitor Aliskiren has been solved using X-ray diffraction at 3.0 angstrom resolution.<ref>PMID: 10903938</ref>
==References==
<references />