MPNNSTALSLANVTYITMEIFIGLCAIVGNVLVICVVKLNPSLQTTTFYFIVSLA LADIAVGVLVMPLAIVVSLGITIHFYSCLFMTCLLLIFTHASIMSLLAIAVDRYL RVKLTVRYKRVTTHRRIWLALGLCWLVSFLVGLTPMFGWNMKLTSEYHRNV.

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Presentation transcript:

MPNNSTALSLANVTYITMEIFIGLCAIVGNVLVICVVKLNPSLQTTTFYFIVSLA LADIAVGVLVMPLAIVVSLGITIHFYSCLFMTCLLLIFTHASIMSLLAIAVDRYL RVKLTVRYKRVTTHRRIWLALGLCWLVSFLVGLTPMFGWNMKLTSEYHRNV TFLSCQFVSVMRMDYMVYFSFLTWIFIPLVVMCAIYLDIFYIIRNKLSLNLSNSK ETGAFYGREFKTAKSLFLVLFLFALSWLPLSIINCIIYFNGEVPQLVLYMGILLSH ANSMMNPIVYAYKIKKFKETYLLILKACVVCHPSDSLDTSIEKNSE PNNSTAL SLANVTYITMEIFIGLCAIVGNVLVICVVKLNPSLQTTTFYFIVSLALADIA VGVLVMPLAIVVSLGITIHFYSCLFMTCLLLIFTHASIMSLLAIAVDRYLRV KLTVRYKRVTTHRRIWLALGLCWLVSFLVGLTPMFGWNMKLTSEYHR NVTFLSCQFVSVMRMDYMVYFSFLTWIFIPLVVMCAIYLDIFYIIRNKLSL NLSNSKETGAFYGREFKTAKSLFLVLFLFALSWLPLSIINCIIYFNGEVP QLVLYMGILLSHANSMMNPIVYAYKIKKFKETYLLILKAC VVCHPSDSLDTSIEKNSE Presented by Lindsay Riley Goddard Group, Caltech SoCalBSI, CalStateLA 20 August 2009

 Good target for  Important to know structure for drug specification  Good target for  Important to know structure for drug specification BACKGROUND G-protein-coupled receptor (GPCR)  7 transmembrane helices  exterior  interior  Involved in many cell signaling pathways BACKGROUND G-protein-coupled receptor (GPCR)  7 transmembrane helices  exterior  interior  Involved in many cell signaling pathways

FUNCTION Prevents restriction of blood flow in brain and heart Anti-inflammatory, anti-cancer effects Protection of spinal cord and bone marrow FUNCTION Prevents restriction of blood flow in brain and heart Anti-inflammatory, anti-cancer effects Protection of spinal cord and bone marrow Kim, S., Jacobson, K. “Three-Dimensional Quantitative Structure – Activity Relationship of Nucleosides Acting at the A3 Adenosine Receptor: Analysis of Binding and Relative Efficacy.” J. Chem. Inf. Model. 2007, 47, THERAPEUTIC IMPLICATIONS A3 ligand (IB-MECA) in Phase II clinical trials for treatment of rheumatoid arthritis and metastatic colorectal tumors THERAPEUTIC IMPLICATIONS A3 ligand (IB-MECA) in Phase II clinical trials for treatment of rheumatoid arthritis and metastatic colorectal tumors

Difficult to perform X-ray crystallography on transmembrane proteins Only 2 / 800 human GPCR structures determined via X-ray crystallography: Bovine rhodopsin Squid rhodopsin Turkey β1-adrenergic receptor Human β2-adrenergic receptor Human A2a-adenosine receptor Difficult to perform X-ray crystallography on transmembrane proteins Only 2 / 800 human GPCR structures determined via X-ray crystallography: Bovine rhodopsin Squid rhodopsin Turkey β1-adrenergic receptor Human β2-adrenergic receptor Human A2a-adenosine receptor

Predict structure using all-atom based first principles methods Predict structure using all-atom based first principles methods GEnSeMBLE Homology Helix 1. Align and homologize 2. Optimize helices 3. BiHelix 4. CombiHelix 5. Analyze top structures 6. SuperBiHelix Final Structure 1. Hydrophobicity profile 2. OptHelix 3. Align to template 4. BiHelix 5. Combihelix 6. Analyze top structures 7. SuperBiHelix Final Structure

MPNNSTALSLANVTYITMEIFIGLCAIVGNVLVICVVKLNPSLQTTT FYFIVSLALADIAVGVLVMPLAIVVSLGITIHFYSCLFMTCLLLIFTHA SIMSLLAIAVDRYLRVKLTVRYKRVTTHRRIWLALGLCWLVSFLVGL TPMFGWNMKLTSEYHRNVTFLSCQFVSVMRMDYMVYFSFLTWIFI PLVVMCAIYLDIFYIIRNKLSLNLSNSKETGAFYGREFKTAKSLFLVLF LFALSWLPLSIINCIIYFNGEVPQLVLYMGILLSHANSMMNPIVYAY KIKKFKETYLLILKAC VVCHPSDSLDTSIEKNSE GEnSeMBLE 1. Align and homologize 2. Optimize helices 3. BiHelix 4. CombiHelix 5. Analyze top structures 6. SuperBiHelix Homology Helix

CLUSTAL multiple sequence alignment sp|P33765|AA3R_HUMAN MPNNSTALSLANVTYITMEIFIGLCAIVGNVLVICVVKLNPSLQTTTFYF 50 sp|P29274|AA2AR_HUMAN MP------IMGSSVYITVELAIAVLAILGNVLVCWAVWLNSNLQNVTNYF 44 ** :...***:*: *.: **:*****.* **..**..* ** sp|P33765|AA3R_HUMAN IVSLALADIAVGVLVMPLAIVVSLGITIHFYSCLFMTCLLLIFTHASIMS 100 sp|P29274|AA2AR_HUMAN VVSLAAADIAVGVLAIPFAITISTGFCAACHGCLFIACFVLVLTQSSIFS 94 :**** ********.:*:**.:* *: :.***::*::*::*::**:* sp|P33765|AA3R_HUMAN LLAIAVDRYLRVKLTVRYKRVTTHRRIWLALGLCWLVSFLVGLTPMFGWN 150 sp|P29274|AA2AR_HUMAN LLAIAIDRYIAIRIPLRYNGLVTGTRAKGIIAICWVLSFAIGLTPMLGWN 144 *****:***: :::.:**: :.* * :.:**::** :*****:*** sp|P33765|AA3R_HUMAN ---MKLTSEYHRN---VTFLSCQFVSVMRMDYMVYFSFLTWIFIPLVVMC 194 sp|P29274|AA2AR_HUMAN NCGQPKEGKNHSQGCGEGQVACLFEDVVPMNYMVYFNFFACVLVPLLLML 194.: * : ::* *.*: *:*****.*:: :::**::* sp|P33765|AA3R_HUMAN AIYLDIFYIIRNKLSLNLSN---SKETGAFYGREFKTAKSLFLVLFLFAL 241 sp|P29274|AA2AR_HUMAN GVYLRIFLAARRQLKQMESQPLPGERARSTLQKEVHAAKSLAIIVGLFAL 244.:** ** *.:*. *:.:.: : :*.::**** ::: **** sp|P33765|AA3R_HUMAN SWLPLSIINCIIYFN---GEVPQLVLYMGILLSHANSMMNPIVYAYKIKK 288 sp|P29274|AA2AR_HUMAN CWLPLHIINCFTFFCPDCSHAPLWLMYLAIVLSHTNSVVNPFIYAYRIRE 294.**** ****: :*...* ::*:.*:***:**::**::***:*:: sp|P33765|AA3R_HUMAN FKETYLLILKACVV CHPSDSLDTSIEKNSE sp|P29274|AA2AR_HUMAN FRQTFRKIIRSHVLRQQEPFKAAGTSARVLAAHGSDGEQVSLRLNGHPPG 344 *::*: *::: *:.* **. :.*:. *.. sp|P33765|AA3R_HUMAN sp|P29274|AA2AR_HUMAN VWANGSAPHPERRPNGYALGLVSGGSAQESQGNTGLPDVELLSHELKGVC 394 sp|P33765|AA3R_HUMAN sp|P29274|AA2AR_HUMAN PEPPGLDDPLAQDGAGVS 412

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MPNNSTALSLANVTYITMEIFIGLCAIVGNVLVICVVKLNPSLQTTT FYFIVSLALADIAVGVLVMPLAIVVSLGITIHFYSCLFMTCLLLIFTHA SIMSLLAIAVDRYLRVKLTVRYKRVTTHRRIWLALGLCWLVSFLVGL TPMFGWNMKLTSEYHRNVTFLSCQFVSVMRMDYMVYFSFLTWIFI PLVVMCAIYLDIFYIIRNKLSLNLSNSKETGAFYGREFKTAKSLFLVLF LFALSWLPLSIINCIIYFNGEVPQLVLYMGILLSHANSMMNPIVYAY KIKKFKETYLLILKAC VVCHPSDSLDTSIEKNSE GEnSeMBLE 1. Hydrophobicity profile 2. OptHelix 3. Align to template 4. BiHelix 5. CombiHelix 6. Analyze top structures 7. SuperBiHelix GEnSeMBLE

Homology Helix

Secondary Structure Prediction | | | | | | SEQ: VGVLVMPLAIVVSLGITIHFYSCLFMTCLLLIFTHASIMSLLAIAVDRYLRVKLTVRYKR PORTER: HHHccHHHHHHHHHHcccccHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHcccccccc PSIPRED: HHHHHHHHHHHHHccccccccHHHHHHHHHHHHHHHHHHHHHHHHHHHEEEEcccccccE OLD_RAW: HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH OLD_CAP: HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH | | | | | | SEQ: SFLTWIFIPLVVMCAIYLDIFYIIRNKLSLNLSNSKETGAFYGREFKTAKSLFLVLFLFA PORTER: HHHHHcHHHHHHHHHHHHHHHHHHHHHHccccccccccccHHHHHHHHHHHHHHHHHHHH PSIPRED: HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHcccccHHHHHHHHHHHHHHHHHHHHHH OLD_RAW: HHHHHHHHHHHHHHHHHHHH HHHHHHHH OLD_CAP: HHHHHHHHHHHHHHHHHHHHHHHHH HHHHHHHHHHH TM2 & TM3 TM6

* Proline and Glycine residues displayed

GEnSeMBLE Homology Helix 1. Align and homologize 2. Optimize helices 3. BiHelix 4. CombiHelix 5. Analyze top structures 6. SuperBiHelix Final Structure 1. Hydrophobicity profile 2. OptHelix 3. Align to template 4. BiHelix 5. Combihelix 6. Analyze top structures 7. SuperBiHelix Final Structure

Dock Ligands DarwinDockMatching GEnSeMBLE Homology Helix Final Structure or

Dock Ligands DarwinDockMatching GEnSeMBLE Homology Helix Final Structure or

adenosine Important residues involved in agonist binding (based on mutation experiments) 6 ASP 7 HIS 3 HIS 7 SER

Also working on… analyzing A3 adenosine docking analyzing A3 SuperBiHelix output A2a structure and ligand docking A1 structure and ligand docking A2b structure and ligand docking docking agonists: ClIBMECA & NECA docking antagonists: MRS1292 & NMeClIBMECA To do list… add loops to final structure simulate lipid bilayer Also working on… analyzing A3 adenosine docking analyzing A3 SuperBiHelix output A2a structure and ligand docking A1 structure and ligand docking A2b structure and ligand docking docking agonists: ClIBMECA & NECA docking antagonists: MRS1292 & NMeClIBMECA To do list… add loops to final structure simulate lipid bilayer

Goddard Group at California Institute of Technology Dr. Soo-Kyung Kim Dr. Ravinder Abrol Professor William A. Goddard III Biogroup SoCalBSI at California State University, Los Angeles Dr. Jamil Momand Dr. Sandy Sharp Dr. Nancy Warter-Perez Dr. Wendie Johnston Ronnie Cheng The lovely interns NIH, Pfizer, PharmSelex