Professional Education

  • Doctor of Philosophy, University of Cambridge (2013)
  • Bachelor of Technology, Vellore Institute Technology (2008)

Stanford Advisors


All Publications

  • Mechanism of intracellular allosteric ?2AR antagonist revealed by X-ray crystal structure. Nature Liu, X., Ahn, S., Kahsai, A. W., Meng, K. C., Latorraca, N. R., Pani, B., Venkatakrishnan, A. J., Masoudi, A., Weis, W. I., Dror, R. O., Chen, X., Lefkowitz, R. J., Kobilka, B. K. 2017; 548 (7668): 480?84


    G-protein-coupled receptors (GPCRs) pose challenges for drug discovery efforts because of the high degree of structural homology in the orthosteric pocket, particularly for GPCRs within a single subfamily, such as the nine adrenergic receptors. Allosteric ligands may bind to less-conserved regions of these receptors and therefore are more likely to be selective. Unlike orthosteric ligands, which tonically activate or inhibit signalling, allosteric ligands modulate physiologic responses to hormones and neurotransmitters, and may therefore have fewer adverse effects. The majority of GPCR crystal structures published to date were obtained with receptors bound to orthosteric antagonists, and only a few structures bound to allosteric ligands have been reported. Compound 15 (Cmpd-15) is an allosteric modulator of the ?2 adrenergic receptor (?2AR) that was recently isolated from a DNA-encoded small-molecule library. Orthosteric ?-adrenergic receptor antagonists, known as beta-blockers, are amongst the most prescribed drugs in the world and Cmpd-15 is the first allosteric beta-blocker. Cmpd-15 exhibits negative cooperativity with agonists and positive cooperativity with inverse agonists. Here we present the structure of the ?2AR bound to a polyethylene glycol-carboxylic acid derivative (Cmpd-15PA) of this modulator. Cmpd-15PA binds to a pocket formed primarily by the cytoplasmic ends of transmembrane segments 1, 2, 6 and 7 as well as intracellular loop 1 and helix 8. A comparison of this structure with inactive- and active-state structures of the ?2AR reveals the mechanism by which Cmpd-15 modulates agonist binding affinity and signalling.

    View details for DOI 10.1038/nature23652

    View details for PubMedID 28813418

  • Diverse activation pathways in class A GPCRs converge near the G-protein-coupling region. Nature Venkatakrishnan, A. J., Deupi, X., Lebon, G., Heydenreich, F. M., Flock, T., Miljus, T., Balaji, S., Bouvier, M., Veprintsev, D. B., Tate, C. G., Schertler, G. F., Babu, M. M. 2016; 536 (7617): 484-487


    Class A G-protein-coupled receptors (GPCRs) are a large family of membrane proteins that mediate a wide variety of physiological functions, including vision, neurotransmission and immune responses. They are the targets of nearly one-third of all prescribed medicinal drugs such as beta blockers and antipsychotics. GPCR activation is facilitated by extracellular ligands and leads to the recruitment of intracellular G proteins. Structural rearrangements of residue contacts in the transmembrane domain serve as 'activation pathways' that connect the ligand-binding pocket to the G-protein-coupling region within the receptor. In order to investigate the similarities in activation pathways across class A GPCRs, we analysed 27 GPCRs from diverse subgroups for which structures of active, inactive or both states were available. Here we show that, despite the diversity in activation pathways between receptors, the pathways converge near the G-protein-coupling region. This convergence is mediated by a highly conserved structural rearrangement of residue contacts between transmembrane helices 3, 6 and 7 that releases G-protein-contacting residues. The convergence of activation pathways may explain how the activation steps initiated by diverse ligands enable GPCRs to bind a common repertoire of G proteins.

    View details for PubMedID 27525504

    View details for PubMedCentralID PMC5008462

  • Visualization and analysis of non-covalent contacts using the Protein Contacts Atlas NATURE STRUCTURAL & MOLECULAR BIOLOGY Kayikci, M., Venkatakrishnan, A. J., Scott-Brown, J., Ravarani, C. J., Flock, T., Babu, M. 2018; 25 (2): 185-+


    Visualizations of biomolecular structures empower us to gain insights into biological functions, generate testable hypotheses, and communicate biological concepts. Typical visualizations (such as ball and stick) primarily depict covalent bonds. In contrast, non-covalent contacts between atoms, which govern normal physiology, pathogenesis, and drug action, are seldom visualized. We present the Protein Contacts Atlas, an interactive resource of non-covalent contacts from over 100,000 PDB crystal structures. We developed multiple representations for visualization and analysis of non-covalent contacts at different scales of organization: atoms, residues, secondary structure, subunits, and entire complexes. The Protein Contacts Atlas enables researchers from different disciplines to investigate diverse questions in the framework of non-covalent contacts, including the interpretation of allostery, disease mutations and polymorphisms, by exploring individual subunits, interfaces, and protein-ligand contacts and by mapping external information. The Protein Contacts Atlas is available at and also through PDBe.

    View details for DOI 10.1038/s41594-017-0019-z

    View details for Web of Science ID 000424521100011

    View details for PubMedID 29335563

    View details for PubMedCentralID PMC5837000

  • Mechanism of Substrate Translocation in an Alternating Access Transporter CELL Latorraca, N. R., Fastman, N. M., Venkatakrishnan, A. J., Frommer, W. B., Dror, R. O., Feng, L. 2017; 169 (1): 96-?


    Transporters shuttle molecules across cell membranes by alternating among distinct conformational states. Fundamental questions remain about how transporters transition between states and how such structural rearrangements regulate substrate translocation. Here, we capture the translocation process by crystallography and unguided molecular dynamics simulations, providing an atomic-level description of alternating access transport. Simulations of a SWEET-family transporter initiated from an outward-open, glucose-bound structure reported here spontaneously adopt occluded and inward-open conformations. Strikingly, these conformations match crystal structures, including our inward-open structure. Mutagenesis experiments further validate simulation predictions. Our results reveal that state transitions are driven by favorable interactions formed upon closure of extracellular and intracellular "gates" and by an unfavorable transmembrane helix configuration when both gates are closed. This mechanism leads to tight allosteric coupling between gates, preventing them from opening simultaneously. Interestingly, the substrate appears to take a "free ride" across the membrane without causing major structural rearrangements in the transporter.

    View details for DOI 10.1016/j.cell.2017.03.010

    View details for Web of Science ID 000397090000011

    View details for PubMedID 28340354

  • Crystal Structure of an LSD-Bound Human Serotonin Receptor. Cell Wacker, D., Wang, S., McCorvy, J. D., Betz, R. M., Venkatakrishnan, A. J., Levit, A., Lansu, K., Schools, Z. L., Che, T., Nichols, D. E., Shoichet, B. K., Dror, R. O., Roth, B. L. 2017; 168 (3): 377-389 e12


    The prototypical hallucinogen LSD acts via serotonin receptors, and here we describe the crystal structure of LSD in complex with the human serotonin receptor 5-HT2B. The complex reveals conformational rearrangements to accommodate LSD, providing a structural explanation for the conformational selectivity of LSD's key diethylamide moiety. LSD dissociates exceptionally slow from both 5-HT2BR and 5-HT2AR-a major target for its psychoactivity. Molecular dynamics (MD) simulations suggest that LSD's slow binding kinetics may be due to a "lid" formed by extracellular loop 2 (EL2) at the entrance to the binding pocket. A mutation predicted to increase the mobility of this lid greatly accelerates LSD's binding kinetics and selectively dampens LSD-mediated ?-arrestin2 recruitment. This study thus reveals an unexpected binding mode of LSD; illuminates key features of its kinetics, stereochemistry, and signaling; and provides a molecular explanation for LSD's actions at human serotonin receptors. PAPERCLIP.

    View details for DOI 10.1016/j.cell.2016.12.033

    View details for PubMedID 28129538

    View details for PubMedCentralID PMC5289311

  • GPCR Dynamics: Structures in Motion CHEMICAL REVIEWS Latorraca, N. R., Venkatakrishnan, A. J., Dror, R. O. 2017; 117 (1): 139-155


    The function of G protein-coupled receptors (GPCRs)-which represent the largest class of both human membrane proteins and drug targets-depends critically on their ability to change shape, transitioning among distinct conformations. Determining the structural dynamics of GPCRs is thus essential both for understanding the physiology of these receptors and for the rational design of GPCR-targeted drugs. Here we review what is currently known about the flexibility and dynamics of GPCRs, as determined through crystallography, spectroscopy, and computer simulations. We first provide an overview of the types of motion exhibited by a GPCR and then discuss GPCR dynamics in the context of ligand binding, activation, allosteric modulation, and biased signaling. Finally, we discuss the implications of GPCR conformational plasticity for drug design.

    View details for DOI 10.1021/acs.chemrev.6b00177

    View details for Web of Science ID 000392036100007

    View details for PubMedID 27622975

  • Structural insights into mu-opioid receptor activation NATURE Huang, W., Manglik, A., Venkatakrishnan, A. J., Laeremans, T., Feinberg, E. N., Sanborn, A. L., Kato, H. E., Livingston, K. E., Thorsen, T. S., Kling, R. C., Granier, S., Gmeiner, P., Husbands, S. M., Traynor, J. R., Weis, W. I., Steyaert, J., Dror, R. O., Kobilka, B. K. 2015; 524 (7565): 315-?
  • Structural insights into ”-opioid receptor activation. Nature Huang, W., Manglik, A., Venkatakrishnan, A. J., Laeremans, T., Feinberg, E. N., Sanborn, A. L., Kato, H. E., Livingston, K. E., Thorsen, T. S., Kling, R. C., Granier, S., Gmeiner, P., Husbands, S. M., Traynor, J. R., Weis, W. I., Steyaert, J., Dror, R. O., Kobilka, B. K. 2015; 524 (7565): 315-321


    Activation of the ?-opioid receptor (?OR) is responsible for the efficacy of the most effective analgesics. To shed light on the structural basis for ?OR activation, here we report a 2.1 Ć X-ray crystal structure of the murine ?OR bound to the morphinan agonist BU72 and a G protein mimetic camelid antibody fragment. The BU72-stabilized changes in the ?OR binding pocket are subtle and differ from those observed for agonist-bound structures of the ?2-adrenergic receptor (?2AR) and the M2 muscarinic receptor. Comparison with active ?2AR reveals a common rearrangement in the packing of three conserved amino acids in the core of the ?OR, and molecular dynamics simulations illustrate how the ligand-binding pocket is conformationally linked to this conserved triad. Additionally, an extensive polar network between the ligand-binding pocket and the cytoplasmic domains appears to play a similar role in signal propagation for all three G-protein-coupled receptors.

    View details for DOI 10.1038/nature14886

    View details for PubMedID 26245379

  • Structural biology. Structural basis for chemokine recognition and activation of a viral G protein-coupled receptor. Science Burg, J. S., Ingram, J. R., Venkatakrishnan, A. J., Jude, K. M., Dukkipati, A., Feinberg, E. N., Angelini, A., Waghray, D., Dror, R. O., Ploegh, H. L., Garcia, K. C. 2015; 347 (6226): 1113-1117


    Chemokines are small proteins that function as immune modulators through activation of chemokine G protein-coupled receptors (GPCRs). Several viruses also encode chemokines and chemokine receptors to subvert the host immune response. How protein ligands activate GPCRs remains unknown. We report the crystal structure at 2.9 angstrom resolution of the human cytomegalovirus GPCR US28 in complex with the chemokine domain of human CX3CL1 (fractalkine). The globular body of CX3CL1 is perched on top of the US28 extracellular vestibule, whereas its amino terminus projects into the central core of US28. The transmembrane helices of US28 adopt an active-state-like conformation. Atomic-level simulations suggest that the agonist-independent activity of US28 may be due to an amino acid network evolved in the viral GPCR to destabilize the receptor's inactive state.

    View details for DOI 10.1126/science.aaa5026

    View details for PubMedID 25745166

    View details for PubMedCentralID PMC4445376

  • Structural basis for chemokine recognition and activation of a viral G protein-coupled receptor SCIENCE Burg, J. S., Ingram, J. R., Venkatakrishnan, A. J., Jude, K. M., Dukkipati, A., Feinberg, E. N., Angelini, A., Waghray, D., Dror, R. O., Ploegh, H. L., Garcia, K. C. 2015; 347 (6226): 1113-1117
  • Structured and disordered facets of the GPCR fold. Current opinion in structural biology Venkatakrishnan, A., Flock, T., Prado, D. E., Oates, M. E., Gough, J., Madan Babu, M. 2014; 27C: 129?37


    The seven-transmembrane (7TM) helix fold of G-protein coupled receptors (GPCRs) has been adapted for a wide variety of physiologically important signaling functions. Here, we discuss the diversity in the structured and disordered regions of GPCRs based on the recently published crystal structures and sequence analysis of all human GPCRs. A comparison of the structures of rhodopsin-like receptors (class A), secretin-like receptors (class B), metabotropic receptors (class C) and frizzled receptors (class F) shows that the relative arrangement of the transmembrane helices is conserved across all four GPCR classes although individual receptors can be activated by ligand binding at varying positions within and around the transmembrane helical bundle. A systematic analysis of GPCR sequences reveals the presence of disordered segments in the cytoplasmic side, abundant post-translational modification sites, evidence for alternative splicing and several putative linear peptide motifs that have the potential to mediate interactions with cytosolic proteins. While the structured regions permit the receptor to bind diverse ligands, the disordered regions appear to have an underappreciated role in modulating downstream signaling in response to the cellular state. An integrated paradigm combining the knowledge of structured and disordered regions is imperative for gaining a holistic understanding of the GPCR (un)structure-function relationship.

    View details for DOI 10.1016/

    View details for PubMedID 25198166

  • Molecular signatures of G-protein-coupled receptors NATURE Venkatakrishnan, A. J., Deupi, X., Lebon, G., Tate, C. G., Schertler, G. F., Babu, M. M. 2013; 494 (7436): 185-194


    G-protein-coupled receptors (GPCRs) are physiologically important membrane proteins that sense signalling molecules such as hormones and neurotransmitters, and are the targets of several prescribed drugs. Recent exciting developments are providing unprecedented insights into the structure and function of several medically important GPCRs. Here, through a systematic analysis of high-resolution GPCR structures, we uncover a conserved network of non-covalent contacts that defines the GPCR fold. Furthermore, our comparative analysis reveals characteristic features of ligand binding and conformational changes during receptor activation. A holistic understanding that integrates molecular and systems biology of GPCRs holds promise for new therapeutics and personalized medicine.

    View details for DOI 10.1038/nature11896

    View details for Web of Science ID 000315137700030

    View details for PubMedID 23407534

  • Deciphering membrane protein structures from protein sequences GENOME BIOLOGY Flock, T., Venkatakrishnan, A. J., Vinothkumar, K. R., Babu, M. M. 2012; 13 (6)


    Co-evolving positions within protein sequences have been used as spatial constraints to develop a computational approach for modeling membrane protein structures.

    View details for DOI 10.1186/gb-2012-13-6-160

    View details for Web of Science ID 000308546300012

    View details for PubMedID 22738306

  • Spial: analysis of subtype-specific features in multiple sequence alignments of proteins BIOINFORMATICS Wuster, A., Venkatakrishnan, A. J., Schertler, G. F., Babu, M. M. 2010; 26 (22): 2906-2907


    Spial (Specificity in alignments) is a tool for the comparative analysis of two alignments of evolutionarily related sequences that differ in their function, such as two receptor subtypes. It highlights functionally important residues that are either specific to one of the two alignments or conserved across both alignments. It permits visualization of this information in three complementary ways: by colour-coding alignment positions, by sequence logos and optionally by colour-coding the residues of a protein structure provided by the user. This can aid in the detection of residues that are involved in the subtype-specific interaction with a ligand, other proteins or nucleic acids. Spial may also be used to detect residues that may be post-translationally modified in one of the two sets of sequences.; supplementary information is available at

    View details for DOI 10.1093/bioinformatics/btq552

    View details for Web of Science ID 000283919800018

    View details for PubMedID 20880955

  • Homomeric protein complexes: evolution and assembly BIOCHEMICAL SOCIETY TRANSACTIONS Venkatakrishnan, A. J., Levy, E. D., Teichmann, S. A. 2010; 38: 879-882


    Homo-oligomeric protein complexes are functionally vital and highly abundant in living cells. In the present article, we review our current understanding of their geometry and evolution, including aspects of the symmetry of these complexes and their interaction interfaces. Also, we briefly discuss the pathway of their assembly in solution.

    View details for DOI 10.1042/BST0380879

    View details for Web of Science ID 000280753600004

    View details for PubMedID 20658970

  • MitoInteractome: Mitochondrial protein interactome database, and its application in 'aging network' analysis 8th International Conference on Bioinformatics Reja, R., Venkatakrishnan, A. J., Lee, J., Kim, B., Ryu, J., Gong, S., Bhak, J., Park, D. BIOMED CENTRAL LTD. 2009


    Mitochondria play a vital role in the energy production and apoptotic process of eukaryotic cells. Proteins in the mitochondria are encoded by nuclear and mitochondrial genes. Owing to a large increase in the number of identified mitochondrial protein sequences and completed mitochondrial genomes, it has become necessary to provide a web-based database of mitochondrial protein information.We present 'MitoInteractome', a consolidated web-based portal containing a wealth of information on predicted protein-protein interactions, physico-chemical properties, polymorphism, and diseases related to the mitochondrial proteome. MitoInteractome contains 6,549 protein sequences which were extracted from the following databases: SwissProt, MitoP, MitoProteome, HPRD and Gene Ontology database. The first general mitochondrial interactome has been constructed based on the concept of 'homologous interaction' using PSIMAP (Protein Structural Interactome MAP) and PEIMAP (Protein Experimental Interactome MAP). Using the above mentioned methods, protein-protein interactions were predicted for 74 species. The mitochondrial protein interaction data of humans was used to construct a network for the aging process. Analysis of the 'aging network' gave us vital insights into the interactions among proteins that influence the aging process.MitoInteractome is a comprehensive database that would (1) aid in increasing our understanding of the molecular functions and interaction networks of mitochondrial proteins, (2) help in identifying new target proteins for experimental research using predicted protein-protein interaction information, and (3) help in identifying biomarkers for diagnosis and new molecular targets for drug development related to mitochondria. MitoInteractome is available at

    View details for DOI 10.1186/1471-2164-10-S3-S20

    View details for Web of Science ID 000272356000020

    View details for PubMedID 19958484

Footer Links:

Stanford Medicine Resources: